RevIewS

B cells, plasma cells and antibody

repertoires in the tumour
microenvironment
George V. Sharonov   1,2,3, Ekaterina O. Serebrovskaya   2,3, Diana V. Yuzhakova   1,
Olga V. Britanova   1,2,3 and Dmitriy M. Chudakov   1,2,3,4*
Abstract | Recent data show that B cells and plasma cells located in tumours or in tumour-draining
lymph nodes can have important roles in shaping antitumour immune responses. In tumour-
associated tertiary lymphoid structures, T cells and B cells interact and undergo cooperative
selection, specialization and clonal expansion. Importantly, B cells can present cognate tumour-
derived antigens to T cells, with the functional consequences of such interactions being shaped
by the B cell phenotype. Furthermore, the isotype and specificity of the antibodies produced by
plasma cells can drive distinct immune responses. Here we summarize our current knowledge
of the roles of B cells and antibodies in the tumour microenvironment. Moreover, we discuss
the potential of using immunoglobulin repertoires as a source of tumour-specific receptors for
immunotherapy or as biomarkers to predict the efficacy of immunotherapeutic interventions.

1
Laboratory of Genomics of
Antitumor Adaptive Immunity,
Privolzhsky Research Medical
University, Nizhny Novgorod,
Russia.
2
Genomics of Adaptive
Immunity Department,
Shemyakin and Ovchinnikov
Institute of Bioorganic
Chemistry, Moscow, Russia.
3
Institute of Translational
Medicine, Pirogov Russian
National Research Medical
University, Moscow, Russia.
4
Center of Life Sciences,
Skolkovo Institute of Science
and Technology, Moscow,
Russia.
*e-mail: chudakovdm@
gmail.com
https://doi.org/10.1038/
s41577-019-0257-x
The importance of T cells in tumour immunosurveil-
lance is well established1–4, but the relative contribution
of B cells has been studied to a much lesser extent,
and mostly only during the past decade. Compared
with T cells, relatively few B cells are usually found in
tumour infiltrates5–8; however, several studies indicate
that their presence and functionality can be consid-
ered as an important prognostic factor in cancer9–19.
Furthermore, plasma cells are present in tumour infil-
trates, and even low counts of these cells are able to
produce large amounts of cytokines20 and antibodies.
These antibodies can promote antitumour immunity
by driving antibody-dependent cellular cytotoxicity
(ADCC) and phagocytosis21,22, complement activa-
tion and enhancing antigen presentation by dendritic
cells23. Moreover, B cells themselves can present anti-
gens to CD4 + and CD8 + T cells and thereby shape
antigen-specific immune responses within the tumour
microenvironment24–26. B cells may also contribute to
the formation of tumour-associated tertiary lymphoid
structures (TLS), which support the further matura-
tion and isotype switching of tumour-specific B cells
as well as the development of tumour-specific T cell
responses27–29.
At the same time, tumour-infiltrating B cells may
exert both protumour and antitumour effects depend-
ing on the composition of the tumour microenviron-
ment and on the phenotypes of B cells present and the
antibodies that they produce (Figs 1,2; Supplementary
Table 1). In this Review, we focus on the B cell and antibody
repertoires that are found in the tumour microenviron-
ment and consider their potential roles as prognostic or
predictive markers and as agents and targets of cancer
immunotherapies.
Tumour-infiltrating B cells
B cells may concentrate at tumour margins7,30 or form
tumour-associated immune aggregates of various com-
plexity, ranging from small unorganized clusters to
structured TLS18,27 (Box 1). The cellular composition of
such structures can differ considerably depending on the
stage and origin of the tumour, as well as other factors,
and has prognostic value in various metastatic and pri-
mary tumours29. In particular, antigen-specific interac-
tions between T cells and B cells in the TLS and in less
organized clusters of tumour-infiltrating lymphocytes
seem to be crucial, and the protective role of T cells in the
tumour microenvironment often depends on coopera-
tion with B cells. The presence of CD20+ B cells close to
CD8+ T cells31 and the colocalization of B cells and T cells
in breast cancer, in malignant melanoma and within
intraepithelial infiltrates from ovarian cancer have
been found to be a positive prognostic marker12,32–34.
Elimination of B cells was shown to suppress the ability
of an anti-GITR antibody to activate an antitumour T cell
response in a mouse model of colorectal and breast car-
cinoma and of a CD73 inhibitor to activate T helper 1
(TH1) and TH17 cells in melanoma35,36. Furthermore,
adoptive co-transfer of ex vivo activated B cells and
T cells in the 4T1 mouse model of breast cancer achieved

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Tumour antigen

IgG1 antibody Neutral cell

FcγR
TAM Tumour-attacking cell

TH1 cell
IFNγ
NK cell
B cell

‘M1-like’ Granzyme B
macrophage ADCC
CD4 +

T cell IgG1 B cell/

MHC
plasmablast/
class II
plasma cell
Phagocytosis
IFNγ, Complement
IL-12

TCR
MHC
class I
CD8+
B cell T cell
IFNγ,
IL-12

CD8+
T cell
Tumour cells

Fig. 1 | Antitumour roles of tumour-infiltrating B cells and intratumourally produced antibodies. B cells and
plasma cells can support antitumour immune responses through several mechanisms. Plasma cell secretion of tumour
cell-specific IgG1 antibodies can mediate antibody-dependent cell cytotoxicity (ADCC) and phagocytosis of tumour cells.
B cells also participate in the presentation of tumour-derived antigens to CD4+ and CD8+ T cells. First, they can directly
present tumour-associated antigens they have captured via B cell receptors. Second, produced antibodies can support
the uptake of tumour antigens by tumour-associated macrophages (TAMs) and dendritic cells. In addition, B cells may
promote antitumour immunity through the release of cytokines that drive cytotoxic immune responses, such as IFNγ and
IL-12. B cells can also directly attack tumour cells using granzyme B and TRAIL (also known as TNFSF10). Immune cells with
antitumour potential are coloured red. FcγR , Fcγ receptor ; NK , natural killer ; TCR , T cell receptor ; TH1 cell, T helper 1 cell.

The Cancer Genome Atlas
(TCGA) database
The most comprehensive
cancer genomics database;
it contains multiple types of
genomic data with histological
information and clinical records
for more than 11,000 patients
and 33 cancer types.
better tumour regression than the transfer of either
population alone37.
The ability of long-lived B cells to serve as antigen-
presenting cells (APCs)38 can essentially explain the pos-
itive outcome of intratumoural B cell–T cell cooperation.
Human ovarian and liver cancer samples contain atypical
populations of mature CD27−IgG+ memory B cells that
express surface markers associated with APCs (namely
MHC class II, CD40, CD80 and CD86) and colocalize
with CD8+ T cells30,32. Although dendritic cells are the
major APCs that provide initial T cell activation in
the  lymph nodes, B cells can maintain additional
T cell population expansion intratumourally by acting
as APCs25,26, or through CD27–CD70 interactions39,
which is important during prolonged inflammatory
response. The evidence that TLS-located B cells may
undergo clonal expansion, somatic hypermutation, iso-
type switching and tumour-specific antibody production
also suggests their active participation in the antitumour
response14,18,29,31,40–43.
Analysis of RNA sequencing (RNA-seq) data from
The Cancer Genome Atlas (TCGA) database revealed that
high levels of expression of B cell and plasma cell sig-
nature genes correlated with increased overall survival
in patients with melanoma, lung adenocarcinoma, pan-
creatic adenocarcinoma, and head and neck squamous
cell carcinoma. By contrast, high levels of expression of
these genes correlated with poorer clinical outcomes
in patients with glioblastoma and clear cell renal cell
carcinoma. High levels of immunoglobulin expression
in tumours is also associated with increased survival in
patients with melanoma42–44, in the proximal proliferative
subtype of lung adenocarcinoma45 and in head and neck
squamous cell carcinoma, but it is associated with poor
prognosis in patients with glioblastoma and renal cell
carcinoma44. These findings are consistent with studies

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Cryptic peptide antigens

Antigens that originate from
translation of sequences
outside annotated open
reading frames. They may
derive from non-annotated
open reading frames,
non-coding genomic regions,
alternative start codons,
frameshift mutations,
alternative splicing or
ribosomal frameshifting.
Protein splicing and
post-translational modifications
can also be classified as cryptic
peptide antigens.
associating plasma cell infiltration with longer survival in
patients with melanoma and non-small-cell lung carci-
noma13,46. In breast cancer, reports on tumour-infiltrating
B cells and plasma cells are to some extent contradic-
tory, with some studies suggesting association with
poor prognosis19,47 and some studies suggesting associ-
ation with better prognosis33 (Supplementary Table 1).
A meta-analysis of non-TCGA transcriptomic data from
~18,000 human tumours found that the relative abun-
dance of intratumoural plasma cells is one of the most
significant positive prognostic factors for patient survival
in the case of various non-brain solid tumours, except for
large-cell lung carcinoma. On the other hand, memory
B cells had negative prognostic value for lung squamous
cell carcinoma, colon cancer and gastric cancer48.
Tumour-specific antibodies
In both the serum and the tumour microenvironment,
antibodies are frequently found that recognize a broad
array of tumour-expressed and self antigens. These
include overexpressed or aberrantly expressed self anti-
gens, unconventionally modified proteins and normal
intracellular molecules. In addition, neoantigens and
cryptic peptide antigens that can drive a humoral immune
response have been identified from immunoscreening of
cDNA libraries from tumour tissues49,50. Such antigens
may originate from a frameshift or replacement muta-
tion, an alternative start codon or alternative splicing
events50–52. Tumour-specific and self-specific antibodies
have been detected in serum from patients with cancer in
numerous studies53–58. Furthermore, estimates of the lev-
els of serum autoantibodies against tumour-associated
and self antigens have been proposed for early detection
of cancer59–63. At later stages of disease, serum antibodies
can serve as potent prognostic markers56,57,64–70.
One well-known tumour-associated antigen, mucin 1
(MUC1), is overexpressed in tumours in an underglyco-
sylated form71–73. Antibodies against MUC1 are detected
in serum from patients at early stages of pancreatic, breast,
gastric, lung and ovarian cancer and serve as a marker

CD4+ TAM
Treg cell
T cell

Tumour cells IL-10

TGFβ
TGFβ

IgA B cell/ IgA

B cell plasmablast/
plasma cell
‘M2-like’
IL-10, macrophage
IL-35
PDL1
PD1
TGFβ IL-10 Effector
Tumour- T cell
associated
neutrophil

Neutral cell
FcR
PMN-MDSC
IgG1 Tumour-
attacking cell

Immunosuppressive
cell
Bispecific IgG4

Fig. 2 | Protumour roles of tumour-infiltrating B cells and intratumourally produced antibodies. B cells and plasma cells
may promote tumour growth through several mechanisms. They can release immunosuppressive cytokines — such as IL-10,
IL-35 and transforming growth factor-β (TGFβ) — that promote immunosuppressive phenotypes in myeloid cells, promote
regulatory T cell (Treg cell) development (thereby reciprocally supporting immunosuppressive B cell formation via TGFβ
production) and suppress or misdirect effector T cell responses. The latter processes may be associated with presentation
of tumour-derived antigens by B cells, resulting in antigen-specific boosting of Treg cells and immunosuppression of effector
T cell responses, potentially strengthened by PDL1 expression. B cells can also produce antibodies that are ineffective
in mediating antitumour responses — that is, antibody classes that do not facilitate antigen presentation or mediate
antibody-dependent cell cytotoxicity and phagocytosis of tumour cells, or IgG1 antibody specificities that do not elicit
efficient T cell response or innate cells attack. At the same time, such antibodies can form immune complexes with
tumour or non-tumour antigens, promoting chronic inflammation, tissue remodelling and eventually immunosuppressive
phenotypes in myeloid cells. FcR , Fc receptor ; PNM-MDSC polymorphonuclear myeloid-derived suppressor cell;
TAM, tumour-associated macrophage.

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Box 1 | Tumour-associated tertiary lymphoid structures
tertiary lymphoid structures (tLs) are typically found at sites of chronic inflammation
and share similarities with lymph nodes. Mature tumour-associated tLs contain
follicle-like structures that have one or more germinal centres with follicular dendritic
cells and proliferating B cells. Germinal centres are surrounded by more disperse T cells,
mature dendritic cells and plasma cells, along with lymphatics and blood vessels18,27,29,176.
some reports indicate that B cells themselves may be involved in the formation of tLs by
producing CXC-chemokine ligand 13 (CXCL13) and lymphotoxin177–179. tLs have been
found in different types of human cancers and usually — but not always — have positive
prognostic value9,29,107,180,181. TLS can be localized in the peritumoural zone and, less
frequently, within the tumour. The latter location has been reported to have a stronger
association with patient survival in pancreatic cancer155. a high density of tumour-
infiltrating B cells was associated with increased survival of patients with pancreatic
adenocarcinoma, but only if they were organized within TLS16. in non-small-cell lung
carcinoma, stromal infiltration by B cells10,17, a B cell-mediated immune response15 and a
high density of TLS germinal centre B cells, in combination with dendritic cell density,
were found to be positive prognostic markers9,14,29. High density of tLs B cells was also
associated with increased CD4+ T cell clonality28. in anti-PD1 therapy for non-small-cell
lung carcinoma, TLS and plasma cells were observed within tumour regression sites159,
and the presence of PD1+CD8+ T cells in TLS was associated with clinical response182.
In high-grade serous ovarian cancer, CD8+ T cell tumour infiltration had no prognostic
value unless combined with the presence of TLS and a high count of plasma cells,
CD4+ T cells and CD20+ B cells. the presence of all these factors simultaneously was
associated with markedly increased survival, with ~65% of patients alive after 10 years18.
the presence of tLs — alongside evidence for intense intratumoural proliferation and
hypermutation of B cells — suggests enhanced local production of effector/memory
B cells and plasma cells that have been trained to recognize tumour antigens29,107.
Consequently, TLS may potentially provide a microenvironment for maturation of an
efficient antitumour humoral response. At the same time, the role of TLS remains
ambiguous, as in an immunosuppressive environment — for example, in the crosstalk
with regulatory T cells, which may be intensified along with tumour progression — the
TLS may also manufacture immunosuppressive cytokines, as well as B cell and TH cell
subsets that are immunosuppressive or suboptimal for antitumour response29,107,183.
of improved prognosis67–70. High serum levels of IgG
antibodies specific for the Thomsen–Friedenreich antigen
(Galβ1–3GalNAcα-O-Ser/Thr) were associated with
longer survival in patients with breast and gastric can-
cer64,68. In general, antibodies against known tumour
antigens are detectable in the serum of approximately
50% of patients with breast cancer74.
There is no universal single origin for tumour-specific
antibodies that are detected in the serum. These antibod-
ies may be produced by plasma cells residing in classical
niches, such as the bone marrow or spleen. However,
there is also evidence that plasma cells may occupy
local tissue niches, especially in the context of chronic
inflammation75,76, and in particular in the tumour micro­
environment46,74. If plasma cells in tumour-associated
TLS produce high levels of tumour-specific antibodies
in situ, these antibodies can also be detected in serum.
On the other hand, there is also evidence of systemic
B cell responses to tumour antigens, as tumour-specific
B cells, plasmablasts and plasma cells can be found in
Thomsen–Friedenreich peripheral blood21,77.
antigen
Intratumoural antibodies were first detected in the
A tumour-associated
carbohydrate antigen highly 1970s78. In 1996, the presence of IgA1 in preparations
expressed by approximately from primary breast cancers and their metastases was
90% of human carcinomas. reported79. Multiple lines of evidence now leave no doubt
It is believed to facilitate that B cells undergo clonal proliferation, selection for
tumour growth by allowing
increased interaction of the
high-affinity antibody and isotype switching within
tumour cells with carbohy- tumour-associated TLS and in less organized struc-
drate-binding lectins. tures, ultimately converting to effector/memory B cells
and antibody-producing plasma cells41,74,80,81. These
plasma cells may reside locally and produce high titres
of tumour-specific antibodies, as has been shown for
breast cancer, melanoma and high-grade serous ovar-
ian cancer31,80,82. In medullary carcinoma of the breast,
tumour-infiltrating B cells were also shown to produce
oligoclonal, somatically mutated anti­bodies that bind
self antigens such as cell surface-exposed actin with
high affinity83. Such antibodies can mediate opsoni-
zation, complement-mediated lysis of cancer cells and
ADCC executed by natural killer (NK) cells or promote
antibody-mediated phagocytosis of tumour cells by
macrophages and granulocytes. In vitro studies have
demonstrated that B cells from patients with melanoma
can produce IgG that is capable of eliminating cancer
cells by triggering ADCC21,22.
Reports showing that infiltration of melanoma and
non-small-cell lung carcinoma by plasma cells13,46 and high
intratumoural immunoglobulin expression in mela-
noma42–44 and head and neck squamous cell carcinoma44
correlate with longer survival indicate the important role
of intratumourally localized plasma cells. Clonal expan-
sion of tumour-infiltrating B cells is also associated with
a more efficient antitumour response42,43,80,83, further
strengthening the idea that focused humoral response
can have important antitumour effects.
Protumour effects of B cells and antibodies
It is important to note that a number of studies in mouse
models have described protumorigenic roles for B cells.
In particular, the growth of syngeneic thymoma, colon
carcinoma and melanoma was significantly slower
in B cell-deficient mice than in wild-type mice or in
B cell-deficient mice that had received adoptively trans-
ferred B cells. B cell-deficient mice were also reported
to show increased T cell infiltration into tumours and
higher levels of TH1 cell-type cytokine production84.
Another study demonstrated an immunosuppressive role
of B cells and B cell-derived IL-10 in mouse models of
lymphoma, melanoma and sarcoma85. In three different
mouse models of prostate cancer, B cell depletion made
mice responsive to the chemotherapy agent oxaliplatin86,
whereas adoptive transfer of B cells restored tumour
growth87. Additionally, antigen-specific anti­tumour vac-
cines were shown to be more effective in the absence of
B cells in mice88,89.
For a number of human cancer types, the presence
of B cells in tumours has also been shown to be an indi-
cator of negative outcome (Supplementary Table 1).
High levels of B cell and/or plasma cell infiltration into
tumours has been associated with increased invasiveness
in bladder cancer90, an increased risk of prostate carci-
noma relapse after prostatectomy91 and reduced survival
of patients with renal cell carcinoma19,44. In some stud-
ies, high rates of plasma cell and CD138+ B cell infil-
tration into tumours were also associated with shorter
recurrence-free survival in patients with invasive breast
carcinoma47. The tumour-promoting effects of B cells
are generally connected with the presence of immuno-
suppressive B cell subsets, often designated as ‘regulatory
B cells’, that may support tumour progression through
various mechanisms (Box 2; Fig. 2; Table 1).
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Immune complexes
Paradoxically, locally or systemically produced
Antigen–antibody complexes, tumour-specific antibodies may also drive tumorigenic
may include multiple antigen effects. In particular, it has been observed that persistent
and antibody molecules, immune complexes formed by tumour-specific antibod-
as well as complement
ies may be associated with unfavourable clinical out-
proteins. They may modulate
activity of myeloid cells, comes65,92,93, potentially due to modulation of activity of
triggering chronic inflammation Fc receptor-bearing myeloid cells. This includes initiation
and tissue remodelling of chronic inflammation, tissue remodelling and angio-
processes, and facilitating
genesis programmes94–97, and favouring — directly or
formation of myeloid-derived
suppressor cells.
indirectly — of myeloid-derived suppressor cell phenotype98.
It can be hypothesized that antibody response to
Myeloid-derived antigens that, first, are not exposed and thus cannot be
suppressor cell recognized on the surface of tumour cells and, second,
An immunosuppressive
myeloid cell that develops
do not contain immunogenic peptides suitable for pres-
under chronic inflammatory entation to T cells on MHC molecules98 may mislead the
conditions. These cells can immune response and thus favour protumour processes.
be subdivided into monocytic This could explain the reported correlation of antibodies
and polymorphonuclear
specific for certain tumour antigens, such as p53, with a
myeloid-derived suppressor
cells.
negative prognosis56,65. Certain antigenic specificities of
serum antibodies were also associated with poor prog-
nosis in ovarian and pancreatic cancer57. Generally, high
levels of immunoglobulin production44 and active isotype
switching99 have been associated with poor prognosis in
renal cell carcinoma (Supplementary Table 1).
Altogether, there is more than sufficient evidence to
show that, in some settings, tumour-infiltrating B cells,
plasma cells and locally produced antibodies may exert
prominent immunosuppressive effects, thereby protect-
ing the tumour against immune-mediated elimination.
An important determinant of whether antibodies have
protumour or antitumour effects is the antibody isotype
present, as we discuss in the following section.
Antibody isotypes in tumours
Human IgG1 antibodies. Antibody functionality is
determined by the constant fragment (Fc) and may be
modulated by various post-translational modifications100.
Box 2 | Immunosuppressive B cells
immunosuppressive or regulatory B cells are characterized by the expression of
inhibitory ligands and cytokines such as IL-10, transforming growth factor-β (tGFβ),
PDL1 (potentially including soluble splice variants184) or lymphotoxin, as well as IL-35,
IL-6, PD1, CD80, CD86, latency-associated peptide (LAP)–TGFβ, FASL, CD40L and
OX40L185–188. immunosuppressive B cells may support tumour progression by inhibiting
the ability of CD4+ and cytotoxic T cells to eliminate tumours84,189, inhibiting natural killer
cell response85, causing regulatory T cell proliferation and generation from naive or
effector CD4+ T cells190,191, modulating the activity of tumour-associated macrophages
and myeloid-derived suppressor cells, and directly promoting tumorigenesis and
angiogenesis (reviewed in ref.187). In renal clear cell carcinoma, a malignancy in which
all studies currently indicate a negative role of activated tumour-infiltrating B cells
(Supplementary Table 1), IL-10-producing B cells were shown to inhibit tumour-
infiltrating T cell function192. B cell-produced iL-35 was reported to be upregulated in
serum from patients with pancreatic cancer and to stimulate the proliferation of
pancreatic cancer cell lines, and more specifically KRASG12D-harbouring neoplastic
lesions193. immunosuppressive B cells may be generated within tumour-associated
tertiary lymphoid structures41 or attracted by the tumour microenvironment — for
example, by the chemokine CXCL13 in prostate and pancreatic cancers87,193.
immunosuppressive B cells have been identified in a variety of different human solid
tumours, including tongue squamous cell carcinoma194, hepatocellular carcinoma108
and gastric cancer195, and are generally associated with a negative prognosis. Advanced
colorectal carcinomas and metastases also contain increased numbers of cells with a
regulatory B cell phenotype, reflecting immune escape196.
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From the perspective of antitumour cytotoxic responses,
the human IgG1 antibody class is of primary importance,
as these antibodies can bind to Fcγ receptor (FcγR)
and trigger ADCC and antibody-mediated phagocy-
tosis and mediate complement-based cytotoxicity101.
Furthermore, FcγR expressed on dendritic cells and
macrophages may capture IgG-bound tumour antigens
and present peptides derived from these antigens to
T cells23,102–105 (Fig. 1).
Maturation of high-affinity antibodies and isotype
switching to IgG1 (ref.106) may occur in TLS located
within or in close to the tumour or in tumour-draining
lymph nodes, and this results in the generation of
plasma cells that may be released into the blood or
reside locally and produce tumour-specific cytotoxic
antibodies29,107. The IgG antibody isotypes, and IgG1
in particular, are often associated with antitumour B
cell activity. The correlation of MUC1-specific and
Thomsen–Friedenreich-specific antibodies with longer
survival is mainly associated with IgG isotypes67,68,70.
Tumour-specific IgG production by plasma cells present
in metastases of patients with high-grade serous ovarian
cancer was also associated with an antitumour response82.
Furthermore, effector and memory B cells expressing
membrane IgG may also execute direct antitumour func-
tions. In hepatocellular carcinoma, it has been shown
that IgG+ memory B cells concentrated in the tumour
invasive margin can produce granzyme B and TRAIL.
These cells also express surface markers characteristic of
APCs, can produce IFNγ and can cooperate with CD8+
T cells, and are correlated with favourable prognosis30.
Likewise, several reports showed that B cell infiltration is
associated with longer survival in patients with hepato-
cellular carcinoma (Supplementary Table 1). At the same
time, accumulation of immunosuppressive B cells may
be a negative factor in the same cancer type108,109.
Using human RNA-seq datasets from TCGA, we
showed that a high proportion of IgG1 isotype RNA
among all intratumourally expressed immunoglobulin
heavy chain (IgH) sequences positively correlates with
non-silent mutation burden in lung adenocarcinoma,
further supporting the role of IgG1+ B cells in antigen
presentation45. Such a high IgG1 proportion was also
strongly associated with longer survival in melanoma43,
KRAS-mutant lung adenocarcinoma, and non-papillary
subtype of bladder cancer45.
IgA, IgD and IgE antibodies. Notably, in the same human
melanoma study of TCGA RNA-seq data, high propor-
tions of IgA, IgD or IgE were associated with a poor
prognosis43. A high intratumoural proportion of the
IgA isotype was also associated with negative prognosis
in the KRAS-mutant subtype of lung adenocarcinoma45.
These observations are in line with those from sev-
eral other publications. High intratumoural IgA level
was found in various human cancers and is associated
with shorter survival in patients with bladder cancer110.
In mouse models, IgA+ plasma cells expressing PDL1 and
IL-10 were shown to impede T cell-dependent responses
on immunogenic chemotherapy for prostate cancer87.
In general, the IgA isotype is often characteristic of the
immunosuppressive B cells involved in the regulatory
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Table 1 | B cell and plasma cell roles in tumours
Cell types Associated effector Roles in the tumour microenvironment
molecules
Immunosuppressive IL-10; TGFβ; Immunosuppression via conversion of
B cells and plasma membrane and soluble CD4+ T cells to Treg cells; suppression of TH1
cells (often IgA+ PDL1; lymphotoxin; cells, CD8+ T cells and NK cells (via PDL1,
plasma cells, mostly IL-35; IgA with IL-10 and IL-35), including in the course of
CD20−/CD19+) unfocused specificity antigen presentation; induce angiogenesis
(via lymphotoxin); promote macrophage
conversion to protumoural M2 phenotype;
stimulation of PMN-MDSC development; no
identified function for produced IgA
IgG1+ plasma cells IgG1 with focused Tumour cell killing via opsonization, complement
specificity (large fixation, ADCC, antibody-mediated phagocytosis;
hypermutating promotion of antigen presentation by dendritic
clones); cytokines cells; drive cytotoxic T cell responses
Effector B cells with Granzyme B, TRAIL; Direct tumour cell killing; antigen-specific
antitumour effects MHC class I, MHC antigen presentation; polarization and education vaccination; clone tumour cell-specific
(often IgG+) class II; IFNγ, IL-12 of CD4+ T cells; TLS formation; dendritic cell
migration; macrophage conversion to tumoricidal
M1 phenotype
ADCC, antigen-specific cell cytotoxicity ; CAR , chimeric antigen receptor ; NK , natural killer ; PMN-MDSC, polymorphonuclear myeloid-derived suppressor cell;
TGFβ, transforming growth factor-β; TH1 cells, T helper 1 cells; TLS, tertiary lymphoid structures; Treg cells, regulatory T cells.
loop in which B cells promote expansion of regula-
tory T cell (Treg cell) populations, while Treg cells produce
transforming growth factor-β (TGFβ), which mediates
isotype class switching to IgA29,111,112 (Fig. 2). This loop
maintains gut homeostasis113–115 and may be naturally
engaged by the immune system to regulate inflammation
of various causes. For example, it has been shown that IgA+
B cells producing IL-10 and expressing PDL1 may accu-
mulate in the liver during chronic inflammation and sup-
press cytotoxic CD8+ T lymphocytes capable of preventing
hepatocellular carcinoma109. Correspondingly, high intra-
tumoural IgA expression levels may be considered as a
biomarker of B cell involvement in the IL-10, TGFβ and
Treg cell pathways, in at least some cancer types or subtypes.
A high proportion of IgE may reflect high intra­
tumoural IL-4 levels and TH cell polarization towards
the TH2 cell fate, which is commonly associated with inef-
ficient tumour control due to suppression of TH1 cell and
cytotoxic T cell response116. IgD antibodies have been
shown to bind to basophils and can drive the production
of factors such as IL-4, IL-5, IL-13, BAFF and APRIL117,118;
as a consequence, high IgD levels may be associated
with IgE and IgA class switching and the generation
of TH2 cells. These effects could potentially explain the
correlation of a high proportion of intratumoural IgE
and IgD with negative prognosis in melanoma43.
IgG4 antibodies. It was shown that IgG4 antibodies,
which are also associated with type 2 immunity119,
lack antitumoural effector functions and may block
tumour-specific IgG1 response120. A high proportion of
IgG4 of all IgG in serum is associated with a poor prog-
nosis in patients with melanoma, and tumour-specific
IgG4 antibodies have been shown to be produced in situ
by plasma cells located within the melanoma lesions121.
A high proportion of IgG4 has also been associated
with favourable prognosis in some cancer types, such as
Possible therapeutic approaches Refs
Remove tumour-infiltrating B cells, 200,204
including CD20− ones (e.g. using
anti-CD19 antibodies); remove IgA+
B cells, including membrane IgA+
plasma cells
Keep and support tumour-infiltrating 29,160,
B cells; promote TLS formation; stimulate 161
NK cells (e.g. by anti-NKG2A , anti-PD1
and anti-PDL1); clone IgG1 for antibody
or CAR T cell therapy ; tumour-associated
antigen/neoantigen vaccination
Tumour-associated antigen/neoantigen 29,160,
161
IgG1 for CAR T cell therapy
lung squamous cell carcinoma122, as well as in STK11-
mutant and proximal proliferative subtypes of lung ade-
nocarcinoma45. The explanation for this positive effect of
IgG4 in particular tumour microenvironments remains
unclear, but we hypothesize that it could be associated
with the inability of IgG4 to form immune complexes123,
which could otherwise stimulate chronic inflammation
and tissue remodelling processes and eventually induce
immunosuppressive myeloid-derived suppressor cell
phenotype94,97,98 (Fig. 2).
IgG3 antibodies. RNA-seq data have suggested that
the relative proportions of IgG3 can be either neutral
or negatively associated with survival in human mela-
noma43, although the reasons for this are unclear. This
is in contrast to IgG1, which has a positive association
with survival for this malignancy, even though both
of these antibody isotypes are capable of triggering
ADCC, phagocytosis, complement activation and anti-
gen cross-presentation. A possible explanation could
be that although IgG3 antibodies can interact with
activating Fc receptors, there is evidence that the IgG3
response is early and transient and that IgG3 antibodies
generally have a lower number of accumulated hyper-
mutations and lower affinity106. Faster turnover of IgG3
antibodies124 can also result in relatively lower local con-
centrations of IgG3 than IgG1, even if both isotypes are
produced at comparable levels.
An alternative explanation comes from the high affin-
ity of monomeric IgG3 for FcγRI (which is expressed
on macrophages) and FcγRIIIA (which is expressed on
both macrophages and NK cells), and especially for the
variant FcγRIIIA-158V (ref.125). Therefore, non-tumour-­
specific, antigen-free IgG3 antibodies may efficiently
occupy vacant FcγRs of NK cells and macro­phages, thus
blocking their interaction with cytotoxic antibodies
bound to the surface of tumour cells (Fig. 3).
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By contrast, non-tumour-specific, antigen-free IgG1
antibodies do not occupy FcγRs, leaving them vacant
and thus allowing IgG1 or IgG3 bound to the surface
of tumour cells to trigger their recognition and elimi-
nation via ADCC and antibody-mediated phagocytosis.
On the surface of tumour cells, avidity increases due to
engagement of multiple receptors (Fig. 3). Furthermore,
allosteric increase of antigen-bound IgG1 affinity for
FcγRs126, still disputable, could enhance productive
ADCC or phagocytic attack127.
In conclusion, the relative abundance of distinct
antibody isotypes in the tumour and tumour-associated
lymphoid structures is an important parameter of the
tumour microenvironment. At the same time, the corre-
lation of distinct antibody isotypes with poor or favour-
able prognoses or response to therapy does not allow one
to discriminate the passive role of isotype as a biomarker
of ongoing processes, in which antibody specificity is of
low importance, and an active role in which antigen spec-
ificity determines the efficiency of cancer surveillance or
promotion. A way to look deeper into this picture is to
analyse intratumoural immunoglobulin repertoires and
clonality, as we discuss next.
Analysing immunoglobulin repertoires
The RNA-based or DNA-based analysis of intratu-
moural T cell receptor and immunoglobulin repertoires
has received increasing attention as a powerful tool for
identifying prognostic and predictive cancer biomarkers,
such as clonality metrics43,77,128. Furthermore, such analysis
allows one to identify therapeutic T cell receptor and anti-
body variants specific for tumour-associated antigens or
neoantigens21,22,31,77,80,83,129. A number of molecular and bio-
informatic tools have been developed to this end, and the
appropriate choice depends on the available material,
time, cost-efficiency and required quality and depth of
immunoglobulin repertoire profiling42,43,130–140 (Table 2).
Of note, immunoglobulin repertoires produced at the
tumour site are often very focused. Up to ~70% of immu-
noglobulin mRNA molecules may belong to a single
clonal group, as has been shown for breast cancer31,40,80,
medullary carcinoma of the breast83, ovarian cancer18 and
melanoma41–43,129, which reflects the presence of clonal
plasma cells producing particular antibody variants.
At the same time, effector B cells may also have a number
of antigen-specific roles (Table 1), which makes analysis of
their repertoire an important part of the whole picture.
The technical complication is that such analysis requires
cell sorting to plasma and memory/effector B cells.
Otherwise, plasma cell immuno­g lobulin sequences
will dominate the repertoire at the RNA level, owing to
their markedly higher expression levels. Alternatively,
a combination of DNA-based and RNA-based immuno-
globulin repertoire profiling would be the informative
way to estimate both B cell clonal and immunoglobulin
functional composition within a tumour sample.

High proportion of IgG3 antibodies High proportion of IgG1 antibodies

FcγR

NK cell
‘M1-like’
macrophage
‘M1-like’ NK cell
ADCC macrophage
ADCC
Phagocytosis

Phagocytosis

Tumour
antigen
Tumour cell

IgG1 IgG3 Tumour-specific Tumour-

IgG1 and IgG3 attacking cell

Fig. 3 | Potential advantages of Igg1-biased over Igg3-biased humoral response. Left panel: due to the high affinity of
monomeric IgG3 for Fcγ receptors (FcγRs) expressed on macrophages and natural killer (NK) cells, high levels of production
of IgG3 (shown in blue) block antigen-specific cell cytotoxicity (ADCC) and antibody-mediated phagocytosis, even
though tumour-specific IgG1 (shown in red) and IgG3 antibodies may also be present in the tumour microenvironment.
Right panel: by contrast, in conditions dominated by the IgG1 isotype, antigen-free IgG1 antibodies do not occupy
FcγRs. The avidity of macrophages and NK cells towards IgG1 bound on the surface of tumour cells increases due to the
engagement of multiple receptors.

Nature Reviews | Immunology

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Table 2 | Pros and cons of methods for extracting immunoglobulin repertoires from cancer samples
Feature Advantages
Starting tissue
Bulk tumour No sorting required; no decrease in sensitivity due to cell loss during tissue
preparation and sorting
Sorted B cells Good reproducibility ; ability to combine B cell RNA-seq and repertoire
profiling
Single B cells Allows pairing of full-length heavy and light chains; semiquantitative in
terms of cells; can be combined with single-cell RNA-seq; full-length chain
extraction available for single-cell RNA-seq with MiXCR
Starting template
DNA Provides information on clonal composition at the level of cells
RNA Provides information on immunoglobulin expression levels; isotype
information preserved
Profiling method
RNA-seq No additional efforts and costsb; ability to work with TCGA and other tumour
or B cell RNA-seq data; full-length chain extraction available for the large
clonotypes with MiXCR
Multiplex PCR High sensitivity, works with medium-quality RNA
5′ RACE Unbiased amplification; high reproducibility
UMI
With UMI Improved quality in long paired-end sequencing; high efficiency in full-length
V(D)J profiling; elimination of most PCR and sequencing errors and biases;
elimination of solid-phase artefacts and contaminants; quantification of
starting molecules offers a control for technical bottlenecks; accurate
normalization of samples in terms of unique molecules analysed
Without UMI No additional step in data analysis
CDR3, complementarity determining region 3; RACE, rapid amplification of cDNA ends; RNA-seq, RNA sequencing; TCGA , The Cancer Genome Atlas; UMI, unique
molecular identifier. aMost highly represented clones can be paired by frequency (ref.145). bIf RNA-seq data are used for general analysis of transcriptome profiles
for tumour or sorted (for example, CD19+) tumour-infiltrating B cells.
Most current work on immunoglobulin repertoire
profiling is based on RNA derived either from the
bulk tumour or from sorted B cell subsets. Targeted
IgH and Igλ/Igκ cDNA libraries can be obtained by
multiplex amplification or 5′ rapid amplification of
cDNA ends, with or without use of unique molecular
identifiers (UMIs; also known as UIDs)130–139. These
can be designed to obtain full-length (from frame-
work region 1 to framework region 4) sequences or
only complementarity-determining region 3 (CDR3)
sequences, or to preserve or discard information about
antibody isotype. These methods differ in terms of sen-
sitivity, accuracy and informativity of obtained reper-
toires and should be properly selected for each particular
task (Table 2).
One recent study of intratumoural immunoglobulin
repertoires with UMI-based CDR3 profiling demon-
strated that there is high clonal overlap, but with nota-
ble differences in the frequency of IgH CDR3 variants,
between the tumour site and adjacent normal mucosal
tissue in colorectal advanced adenoma and colorectal can-
cer. In comparison, much greater CDR3 repertoire homo­
geneity was observed across different segments of healthy
colon141. These results may reflect clonal proliferation and
plasma cell generation at the tumour site.
On the basis of non-targeted tumour or sorted B cell
RNA-seq data, one can also identify prognostic signatures
Disadvantages
Low reproducibility if tumour infiltration is low;
unpaired repertoirea
Requires cell sorting; sorting may decrease
sensitivity due to cell loss; unpaired repertoirea
Low throughput, superficial profiling; expensive;
low reproducibility
Information on expression levels lost; isotype
information lost
No information on clonal composition at the level
of cells
Prominent tumour infiltration is a prerequisite,
although even minor presence of plasma cells may
be sufficient to capture highly represented CDR3
RNA reads; superficial profiling
Quantitative biases
Lower sensitivity than multiplex PCR; requires
high-quality RNA
Additional step in data analysis (e.g. with MiGEC137
or MiNNN)
Lots of errors; low efficiency in full length V(D)J
profiling; uncontrolled depth of profiling
of intratumoural immunoglobulin repertoires33,44,142. In
particular, assessment of the degree of clonality — that
is, the presence of large clonal expansions — in the intra-
tumoural immunoglobulin repertoire, as well as the
amount of somatic hypermutations in immunoglobulin
gene segments, can offer prognostic value for some
types of cancer. Analysis of IgH repertoires extracted
from TCGA RNA-seq data from melanoma samples has
revealed that survival is highest for patients with high
immunoglobulin expression and clonality42,43, where
clonality reflects mainly the presence of plasma cell
clonal expansion, as discussed above. Clonality had a
much stronger association with survival: the combination
of high immunoglobulin expression (that is, numerous
plasma cells at the site) and low clonality, which could
be interpreted as absence of a distinct antigen-specific
response, resulted in an equally poor prognosis as low
immunoglobulin expression, while low immunoglobu-
lin expression and high clonality resulted in an average
prognosis. Although high immunoglobulin expression
and a high proportion of the IgG1 isotype has been asso-
ciated with a better prognosis, the combination of these
two parameters with high IgH clonality was not associ-
ated with further improvements in survival prognosis for
TCGA patients with melanoma43. This can be explained
by the fact that a high IgG1 proportion correlates with
the presence of large clonal expansions, such that the two
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parameters are essentially dependent. In contrast, a high
IgA proportion correlates with low clonality, suggesting
that, in melanoma, B cell switching to the IgA isotype is a
passive consequence of the intratumoural cytokine envi-
ronment and is not driven by particular antigens. Large
clusters of hypermutating immunoglobulin subvariants
are also predominantly formed by IgG1 antibodies43.
IgG1 repertoires are characterized by high clonality and
intense hypermutation in samples either with or without
lymph node material43, reflecting the presence of TLS and
correlating with increased AID expression, as has been
reported in melanoma129.
Intratumoural expression levels, proportions, clon-
ality and extent of hypermutation for the IgG1, IgA,
IgE and IgD isotypes in melanoma are thus compo-
nents of the same picture. A focused immune response
driven by the appropriate environment and available
immunogenic tumour antigens leads to the genera-
tion of large plasma cell clones producing high-affinity,
tumour-specific IgG1 antibodies, while an immunosup-
pressive environment leads to B cells switching to IgA
and other isotypes that usually exhibit less focused spec-
ificity but with higher potential for cytokine-mediated
immunosuppression.
Of note, this scenario may be typical of human mela-
noma, but could be different for other cancers. Although
a high IgG1 proportion is specifically beneficial for
KRAS-mutant lung adenocarcinoma, high IgG1 clonality
remains a neutral parameter45. This observation may indi-
cate that IgG1+ B cells play a positive role in this cancer
subtype via antigen presentation or direct attack of tumour
cells, rather than through ADCC or antibody-mediated
phagocytosis, since the latter would require a highly
clonal IgG1 repertoire produced by plasma cells at the
RNA level, as seen with melanoma. As KRAS-specific
B cells143 and CD4+ T cells144 have been recently identi-
fied, an attractive interpretation that still requires fur-
ther investigation is that in KRAS-mutant tumours, the
IgG1 shift of tumour-infiltrating B cells could lead to
more efficient presentation of the mutant KRAS peptide
itself — along with other tumour-associated antigens and
neoantigens — thus attacking the tumour in the most
vulnerable spot.
Recovering functional antitumour antibodies
Both tumour-infiltrating and circulating B cells and
plasma cells have been shown to be a potent source of
antibodies that recognize autologous tumours as well as
some heterologous tumours — predominantly those of
the same tissue origin21,22,31,77,80,82,83. To recover functional
antitumour antibodies via high-throughput sequencing,
it is crucial to obtain full-length and error-free immuno­
globulin sequences and to accurately pair light and
heavy chains from each antibody of interest. For the
largest intratumoural immunoglobulin-producing
plasma cell clones, information on full-length IgH
and Igκ or Igλ light chains can be extracted from tar-
geted immunoglobulin-sequencing data139 or RNA-seq
data42,43. The latter option was recently upgraded in
MiXCR. The resulting heavy and light chains can be
paired on the basis of frequency matching145. Because
some of the largest IgG1 clonotypes could play an
Nature Reviews | Immunology
Reviews
important role in cancer surveillance, the RNA-seq-
based approach could be directly used in cancer immu-
notherapy using autologous or allogeneic cytotoxic
antibodies or chimeric antigen receptor (CAR) T cells.
Implementation of microfluidic emulsion-based
approaches can provide a comprehensive analysis of
paired heavy and light immunoglobulin chains expressed
by hundreds and thousands of individual B cells146.
The combination of molecular barcoding and droplet
barcoding is crucial for providing increased accuracy
of analysis. This approach was recently applied to the
analysis of tumour-infiltrating lymphocytes in ovarian
cancer147, revealing ~6,000 immunoglobulin pairs per
400,000 unsorted tumour cells that entered the emulsion
reaction. In general, the rapid development of single-cell
analysis approaches, especially those based on emulsion
techniques148, is revealing new avenues for both immuno­
globulin repertoire and transcriptomic profiling of
tumour-infiltrating B cells, allowing pairing of heavy and
light chains of immunoglobulins146,149 as well as linkage
of the repertoire with antigenic specificity150 and the
single-cell transcriptome.
A remarkable example is a recent work in which
New York oesophageal squamous cell carcinoma 1
(NY-ESO-1)-specific antibodies were successfully
identified in breast cancer by single-cell analysis of
B  cells taken from tumour-draining lymph nodes.
Several reconstituted antibodies were cloned and shown
to be affinity maturated against NY-ESO-1 and were also
found in the circulation by affinity chromatography
enrichment and mass spectrometry151.
The microfluidic methods are still relatively laborious
and expensive and thus are currently limited to relatively
small numbers of samples and cells. Nevertheless, these
powerful approaches could help reveal the functional
heterogeneity of tumour-infiltrating B cells and sug-
gest rational therapeutic approaches that canalize their
functionality towards desirable antitumour action. In the
future, direct single cell-based clinical applications
may become possible that allow rapid identification
of tumour-specific IgG1 antibodies for use in cancer
immunotherapy.
Therapeutic targeting of B cells in tumours
As discussed already, a number of studies indicate that
B cells and plasma cells may often play a protumour role
in the tumour microenvironment, and this has prompted
the development of therapeutic approaches based on
B cell depletion in solid cancers93,152,153 (Box 3). However,
as we have also discussed in this Review, B cells may exert
potent antitumour effects, with notable interspecies dif-
ferences that can make such effects challenging to model
in mice. In relatively short-term tumour transplantation
models, TLS may not form or may have defective struc-
tures154, which may in turn account for the prevalence of
protumoural functions of B cells reported in mice mod-
els. By contrast, in human cancers, immune-activating,
tumour-suppressing B cells are often organized in intra-
tumoural TLS, the appearance of which is associated
with favourable prognoses for many cancers9,14,29,155.
Thus, B cell depletion may have deleterious conse-
quences for a large subset — and potentially a majority
Reviews
Box 3 | B cell depletion in solid cancers
For those types and subtypes of solid cancers (for example, clear cell renal cell
carcinoma; supplementary table 1) or narrowly specified cohorts of patients where
B cell depletion could have clinical benefit, the method used to eliminate or suppress
B cells should be chosen carefully. Early animal studies provided motivation for the use
of B cell-depleting anti-CD20 antibodies such as rituximab or ofatumumab as an
adjuvant for treatment of solid tumours. However, clinical data have shown that
neoadjuvant therapy with rituximab had no effect following iL-2 therapy for
metastatic renal cell carcinoma and melanoma197. anti-CD20 depleting antibodies
were also used in an adjuvant setting to treat 10 patients with metastatic melanoma198.
this treatment significantly decreased overall inflammation and tumour infiltration
by CD8+ T cells and macrophages, and did not suppress tumour progression. Several
other clinical trials involving patients with melanoma treated with rituximab
(Clinicaltrials.gov identifiers NCt01032122 and NCt02142335) were either
terminated or completed without results being reported. One more trial of rituximab
for treatment of solid tumours is now in progress, with the aim of depleting
tumour-infiltrating B cells in prostate cancer (NCt01804712). intratumoural
immunosuppressive B cells are typically classified either as regulatory B cells (typically,
as producing iL-10 and tGFβ) or iL-10-producing plasma B cells (often iga+, also
expressing PDL1 and tGFβ). Regardless, these cells are usually CD20– (refs87,199),
and thus the clinical failure of anti-CD20-based efforts to deplete intratumoural
B cells197,200 is unsurprising. Bispecific T cell-engaging anti-CD19/anti-CD3 antibodies
such as blinatomumab or CD19-targeting chimeric antigen receptor T cells, both of
which are now widely used in B cell malignancies, could be a superior method for
eliminating all B cells, including immunosuppressive B cells and plasma cells.
Long-living plasma cells may lose expression of CD19 as well201. However,
immunosuppressive CD19− tumour-associated plasma cells have not yet been
reported. Several alternative targets to CD19 remain as well, including CD38
(refs202,203), CD138 and surface IgA, as human IgA+ plasma cells (unlike igG+ plasma
cells) retain a functional membrane B cell receptor204. small synthetic drugs such as
ibrutinib are another option for suppressing B cells. Ibrutinib targets BTK, a critical
mediator of signalling by B cell receptor and other receptors (FcγRs, Toll-like
receptors, G protein-coupled receptors) as well as B cell survival, migration and
differentiation into plasma cells. ibrutinib has been used in several clinical trials as a
monotherapy or in combination with other therapies to treat various solid tumours205.
ibrutinib significantly increases survival in combination with chemotherapy or
immunotherapy. However, the role of B cells in this effect is not clear, as ibrutinib has
also been shown to affect intratumoural myeloid cells and enhance t helper 1 cell
skewing of CD4+ T cells206,207. inhibitors of the BaFF/aPriL system208 also represent
unexplored options for immunotherapeutic intervention in solid cancers where
suppression of B cell activity could be desirable. there is also interest in rational
combination of B cell-depleting therapy with other immunotherapeutic approaches.
The existence of a natural loop between IgA-producing B cells and regulatory T cells
(Fig. 2) suggests that simultaneous targeting of the two subsets could be beneficial —
for example, by combining cytotoxic anti-GITR antibodies targeting regulatory T cells
with anti-CD19 therapy. On the other hand, a study on a mouse model suggested
that anti-GITR therapy activates B cells, which was a crucial part of response to this
immunotherapy35. this observation confirms once again that total B cell depletion
is a 1D intervention and should be applied to only very specific cohorts of patients for
whom the role of B lymphocytes is shown to be clearly negative.
— of patients, and strategies for rational patient stratifi-
cation for B cell-related therapies are therefore required.
Such stratification could be based on the abundance of
IL-10-producing B cells in tumours or tumour-draining
lymph nodes, as estimated by immunohistochemistry or
flow cytometry. Measuring the serum or tumour abun-
dance of tumour-specific antibodies or B cells that are
associated with a negative clinical outcome56,57,65,66 could
also potentially inform B cell-depleting therapies.
Alternative strategies should prevail for the cate-
gories of patients in which tumour-associated B cells,
plasma cells and antibody specificities reinforce the
immune system against cancer. For some cancer types,
this can be determined on the basis of high antibody
clonality, dominance of the IgG1 isotype, hypermutation
intensity and the spectrum of cytokines and costimu-
latory molecules they produce, as well as abundance
of tumour-specific antibodies associated with positive
clinical outcome57,64,67–70.
Considering ADCC as one of the direct mechanisms
of antigen-specific antitumour B cell response, immuno­
therapeutic agents that stimulate NK cells —such as
monalizumab, a monoclonal antibody to NKG2A,
which serves as a checkpoint inhibitor for NK cells156
— should contribute to a more pronounced response
for patients with a highly focused IgG1 repertoire of
tumour-associated plasma cells. Activation of (probably
clonal) NK cell populations with anti-PD1 therapy157,158
suggests that the combination of B cell-promoting and
PD1-blocking therapies could be beneficial owing to
synergistic effects on B and T cells as well as B and NK
cells. Notably, immune-mediated tumour clearance in
neoadjuvant anti-PD1 therapy for non-small-cell lung
carcinoma was associated with local formation of TLS
and the presence of plasma cells159. More recent stud-
ies have also demonstrated prominent association of
responsiveness to immune checkpoint blockade with
the presence of TLS and clonal B cell expansion in
melanoma160,161, and of TLS and B cells in soft-tissue
sarcomas162. Anti-CTLA4 therapy was shown to nota-
bly increase the number of circulating plasma cells
in non-progressing patients with metastatic cancer77.
In the context of the largely CD4+ T cell-supporting out-
come of anti-CTLA4 therapy3, this effect suggests that
CD4+ T cell-mediated stimulation of antibody affinity
maturation and plasma cell generation could induce
tumour-associated B cells that produce tumour-specific
antibodies in local and draining lymph nodes and TLS.
Vaccination trials have also demonstrated the induction
of TLS formation29,163,164.
Analysis of intratumoural compositions of immuno­
globulin repertoires could help in patient stratification
for different types of B cell-targeting therapy, either
individually or at the level of particular cohorts. For
melanoma, the intratumoural presence of large hyper-
mutating clonal IgG1 expansion — reflecting affin-
ity maturation and antigen-driven proliferation of
immunoglobulin repertoires produced in situ within
tumour-associated TLS and draining lymph nodes —
is associated with longer patient survival14,18,31,40–43. This
most probably results from efficient tumour control by
ADCC or antibody-mediated phagocytosis, suggesting
that therapeutic approaches that support these mecha-
nisms, promote TLS function and shift B cells towards
the IgG1 isotype should be generally beneficial for
patients with melanoma.
However, the whole picture for different cancers
seems to be more complicated. The established mode
of tumour-immunity interactions may differ for dis-
tinct functional subtypes of a certain cancer, as cur-
rently classified on the basis of tumour mutational
load, extent of infiltration by immune cells, abundance
of cancer-associated fibroblasts, angiogenesis, tumour
proliferation rate, cancer signalling pathways and other
gene signatures and histological features165–168. Notably,
the established type of tumour–immune interaction may
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 Reviews

also be influenced by driver mutations associated with
particular modes of immune response169–172.
Furthermore, there may be other specific tumour
features, such as particular mechanisms of immune
suppression and escape, as well as the presence and
abundance of immunogenic tumour antigens that elicit
efficient antitumour responses or, conversely, that mis-
lead the immune system, triggering prominent but sub-
optimal B cell and T cell responses. Dominant isotypes
of antibodies specific to particular tumour antigens and
the presence of tumour antigen-specific clonal popu­
lations of T cells and B cells of a particular functionality —
including Treg cells and regulatory B cells — further add
to the complexity of the whole picture. This latter con-
sideration makes the ability to identify tumour-specific
immunosuppressive T and B cells highly desirable.
Correspondingly, we should expect that the roles of
tumour-infiltrating B cells, and thus the prognostic and
predictive significance of immunoglobulin repertoires,
will differ for different cancer subtypes. Indeed, the classifi-
cation of tumours into molecular subtypes often correlates
with the prognostic value of B cell and immunoglobulin
repertoire features (Supplementary Table 1).
A remarkable example is the distinct prognostic
role of immunoglobulin repertoires in subtypes of lung
cancer. As already mentioned, a high ratio of intra-
tumoural IgG1 to IgA is specifically associated with
longer survival in KRAS-mutant adenocarcinoma but
not in wild-type KRAS adenocarcinoma, while abun-
dance of IgG4 is associated with a favourable prognosis
in squamous cell carcinoma122 and in STK11-mutant
and proximal proliferative adenocarcinoma45. Positive
prognosis was also associated with high IgH expression
level and high IgH to MS4A1 (which encodes CD20)
expression ratio specifically for proximal proliferative
lung adenocarcinoma45.
Immune infiltration of breast and ovarian cancers
is highly dependent on molecular subtype. Activated
B cells and IgG gene signatures are enriched and have
significant prognostic value only in those subtypes that
have high overall immune infiltration (namely basal and
HER2 enriched for breast cancer, and immunoreactive
and mesenchymal for ovarian cancer), reflecting tight
cooperation of B cells with other immune cells33.
Altogether, it seems that an appropriate classification
strategy for tumour subtypes needs to be developed —
considering immunoglobulin repertoires as one of the
critical parameters — wherein distinct B cell phenotype
and antibody isotype content, clonality and specificity
will ultimately dictate the rationale for different com-
binations of immunotherapeutic interventions. Where
possible and appropriate, one component of such com-
bination therapies could include antitumour antibodies
or CAR T cells of deficient specificities. Thus, identifica-
tion and demonstration of clinical utility of novel thera-
peutic tumour-specific antibodies capable of recognizing
tumour antigens in a relatively broad spectrum of patients
— with the aim of depleting tumour cells and/or boost-
ing efficient tumour-specific T cell response — remains a
highly attractive and potentially feasible goal173–175.
Conclusion
In this Review, we have emphasized that B cells are not
simply bystander cells in the tumour microenvironment
but are instead active participants that can fundamen-
tally orchestrate the immune response. B cells can pro-
tect against tumours under certain conditions, mainly
through the production of tumour-specific antibodies
and presentation of tumour antigens, but certain B cell
subsets and antibody specificities can also suppress
anticancer immunity and promote tumour growth. The
existence of such opposing effects can be explained by
the influence of different intratumoural contexts, which
polarize B cells to distinct functional phenotypes, as well
as the distinct consequences of immune reactions to dif-
ferent types of immunogenic tumour antigen. Different
functional populations of B cells, antibody isotypes and
antigenic specificities could enhance or diminish ADCC
and antibody-dependent phagocytosis, provide desira-
ble or undesirable modes of antigen presentation, or
contribute to the generation of immune complexes with
potentially immunosuppressive impacts.
Systematic characterization of antibody expression,
spatial localization and functional phenotypes of intra-
tumoural and nearby B cells and their interactions with
other cells may provide new insights into the role of
B cells in tumour immunology and expand our ability
to rationally manage these roles in distinct, properly
classified cancer subtypes.
The ambiguous role of B cells in the tumour environ-
ment predetermines the multidirectional development
of immunotherapeutic approaches, either supporting
positive B cell types and specificities or providing defi-
cient specificities or else suppressing negative B cell types
and their associated processes and antibody specificities.
As a consequence, decisions related to the application
of B cell-targeted therapies and their combination with
other therapies should be based on a deep understand-
ing of the prevailing nature of B cell participation in
tumour–immune interactions in each cancer subtype
or even in each patient. Our ability to analyse, rationally
interpret and use immunoglobulin repertoire data from
tumour-associated B cells is becoming an important part
of this story.
Published online xx xx xxxx

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Author contributions
All of the authors contributed to researching data for the
article, the discussion of content and the writing of the article.
D.M.C. and G.V.S. reviewed and edited the manuscript before
submission.
Competing interests
The authors declare no competing interests.
Funding
The work was supported by grants from the Ministry of
Education and Science of the Russian Federation (14.W03.
31.0005) and Russian Science Foundation (19-14-00317, in
part of antibody repertoire analysis methods).
Peer review information
Nature Reviews Immunology thanks K. Willard-Gallo and
the other, anonymous, reviewer(s) for their contribution to the
peer review of this work.
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Supplementary information
Supplementary information is available for this paper at
https://doi.org/10.1038/s41577-019-0257-x.
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