Seminars in Cancer Biology 65 (2020) 189–196

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Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

Tumor intrinsic and extrinsic immune functions of CD155 T

a b b b,
Jake. S. O’Donnell , Jason Madore , Xian-Yang Li , Mark J. Smyth *
a
Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, QLD, Australia
b
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia

A R T I C LE I N FO A B S T R A C T

Keywords: CD155 (PVR/necl5/Tage4), a member of the nectin-like family of adhesion molecules, is highly upregulated on
Cancer tumor cells across multiple cancer types and has been associated with worse patient outcomes. In addition to
CD155 well described cell-intrinsic roles promoting tumor progression and metastasis, CD155 has now been implicated
PVR in immune regulation. The role of CD155 as a potent immune ligand with diverse cell-extrinsic functions is now
Immunotherapy
being defined. CD155 signaling to immune cells is mediated through interactions with the co-stimulatory im-
mune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96, which are differ-
entially regulated at the cell surface on T cells and NK cells. The integration of signals from CD155 cognate
receptors modifies the activity of tumor-infiltrating lymphocytes in a context-dependent manner, making CD155
an attractive target for immune-oncology. Preclinical studies suggest that targeting this axis can improve im-
mune-mediated tumor control, particularly when combined with existing anti-PD-1 checkpoint therapies. In this
review, we discuss the roles of CD155 on host and tumor cells in controlling tumor progression and discuss the
possibility of targeting CD155 for cancer therapy.

1. Introduction
The ability of tumors to escape or locally suppress the immune
system is fundamental for their development [1,2]. Cancer im-
munotherapies targeting the PD-1/PD-L1 or CTLA4 immune check-
points function by relieving immune suppression or promoting immune
activation, and have achieved durable efficacy for some patients across
multiple tumor indications [3–5]. While more effective than che-
motherapies, and with greater ability to induce long-term durable re-
sponses than those seen with targeted therapies (BRAF/MEK inhibi-
tion), existing cancer immunotherapies are nevertheless associated with
innate and acquired resistance [3–6]. As such, the identification of al-
ternative approaches and targets that may improve responsiveness
when used in combination with existing immunotherapies is a current
priority. One attractive target is immune regulatory functions of the cell
adhesion molecule CD155 (Poliovirus receptor [7]). CD155 is com-
monly over-expressed by tumor cells and upregulated by tumor-asso-
ciated myeloid cells in both membrane bound and soluble forms [8,9]
where its tumor cell-intrinsic roles, which include promoting cell to cell
adhesion [10], cell motility [10–13], contact inhibition [14], pro-
liferation, and survival [15] have implicated it in tumor progression.
More recently, CD155 has been shown to play important tumor cell-
extrinsic roles by modulating the function of tumor-infiltrating
lymphocytes via interactions with both stimulatory and inhibitory re-
ceptors on T and NK cells [16] (Fig. 1B). In this review we will discuss
evidence that CD155 expression contributes to tumor development
through tumor-associated immune suppression, how this immune sup-
pression impacts responsiveness to cancer immunotherapy, and why
targeting CD155 and its associated axis might be beneficial for cancer
treatment.
2. Cell-intrinsic biology of CD155
The Nectins and Nectin-like molecules (Necl) are a family of Ig-like
proteins that play important roles in supporting cell to cell adhesion via
homophilic and heterophilic interactions between family members.
Necl5, also known as CD155 was originally defined as a receptor to
permit poliovirus entry [8,17], however, work by several groups ulti-
mately implicated CD155 in a suite of physiological/pathophysiological
processes [14]. The extracellular region of CD155 contains im-
munoglobulin V domains, a C1-like domain, and a C2 domain [14].
There are four splice isoforms designated α, β, δ, and γ. The α and δ
isoforms contain transmembrane domains, with the α isoform con-
taining a longer C terminus and an immunoreceptor tyrosine-based
inhibitory motif (ITIM) that is necessary for CD155-signaling and its
tumor cell-intrinsic biology (Fig. 1A). By contrast, the β and γ isoforms

⁎
Corresponding author.
E-mail address: mark.smyth@qimrberghofer.edu.au (M.J. Smyth).

https://doi.org/10.1016/j.semcancer.2019.11.013
Received 26 September 2019; Received in revised form 6 November 2019; Accepted 19 November 2019
Available online 26 December 2019
1044-579X/ © 2019 Elsevier Ltd. All rights reserved.
J.S. O’Donnell, et al. Seminars in Cancer Biology 65 (2020) 189–196

Fig. 1. The tumor cell intrinsic and extrinsic roles of CD155.

(A) The intracellular domain of CD155 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) capable of recruiting SH2-containing tyrosine phos-
phatase-2 to initiate signal transduction by acting as a mediator of the important cellular functions of CD155 including adhesion, contact inhibition, cellular motility,
proliferation, and survival. Many of these functions are achieved through simple interactions with other members of the immunoglobulin superfamily. For example,
CD155 can interact with growth factor receptors such as platelet-derived growth factor receptor (PDGFR) where it can enhance growth-factor mediated Ras-Raf-MEK-
ERK signaling, and also with integrin αvβ3 to enhance cellular migration. (B) CD155 expressed by tumor and tumor-associated myeloid cells can interact with at least
three lymphocyte-expressed receptors to modulate their effector functions. The inhibitory checkpoint receptors TIGIT and CD96 are upregulated by T and NK cells
following activation and increasingly when exposed chronically to antigen in settings such as cancer and chronic viral infection. These receptors and compete with
the costimulatory receptor DNAM-1 for binding to CD155 and function over time to diminish T and NK cell functionality in the tumor microenvironment. In NK cells,
interactions between α1β2 integrins (LFA-1) and DNAM-1 appear to be necessary for DNAM-1-mediated NK cell activation.

lack a transmembrane domain and are secreted, however, the biological
function of these isoforms has not been clarified [18]. The CD155α
ITIM domain can recruit important signaling intermediates such as
SH2-containing tyrosine phosphatase-2 (SHP-2) to initiate signal-
transduction [11,19]. The initiation of signaling by CD155 is usually
preceded by its interaction with either with other nectins, growth factor
receptors, or integrins [15,20,21] (Fig. 1A). Collectively, these sig-
naling inputs enable the cell-intrinsic roles of CD155 in promoting
cellular proliferation, migration, contract inhibition, and survival; im-
plicating tumor cell-intrinsic CD155 in promoting tumor progression,
invasion, and metastasis.
The signaling outputs of CD155 have been proposed to have mul-
tiple effects in the context of cancer. For instance, an in vitro screen
identified that knock-down of CD155 significantly reduced tumor cell
migration [22,23]. In one study, CD155 was shown to play an essential
role in growth factor-mediated cell migration. This effect was found to
depend on the co-localisation of CD155 αVβ3 integrins at the leading
edge of migrating cells and the indication of intracellular signaling via
Rac and Cdc42, which have well-defined roles in cell migration. In
addition to migration, CD155 has been shown to promote tumor me-
tastatic spread [23]. Over-expression of CD155 in rat glioma cells was
shown to increase Src and focal adhesion kinase signaling, which in
turn reduced substrate adhesion and promoted cell spreading [24].
Subsequently, observations made using mouse tumor models support
this conclusion, where CD155-expressing tumor cells have been shown
to have greater metastatic potential than tumor cells in which CD155
has been knocked out [9]. CD155 signaling also appears to be important
for tumor cell proliferation. Tumor cells in which CD155 has been
knocked-out demonstrate defects in proliferation, cell cycle arrest [25].
3. Cell-extrinsic biology of CD155
The overexpression of CD155 seen in many tumor types was ori-
ginally hypothesized to act as an extrinsic tumor-suppressor mechanism
capable of alerting the immune system that a tissue had undergone
malignant transformation [8]. This hypothesis was born-out of the
observation that the co-stimulatory receptor CD226 or DNAX Accessory
Molecule-1 (DNAM-1) expressed by T and NK cells interacts directly
with CD155 and the closely related CD112 (Nectin-1) molecules to
promote their activation [26]; the latter of which can also bind
CD112R, a checkpoint receptor expressed by T cells [27]. These inter-
actions were shown to trigger NK cell- and T cell-mediated cytotoxicity
and cytokine production [28,29]. In addition, mice genetically deficient
in DNAM-1 demonstrated significantly less anti-tumor activity against
CD155 positive tumor cells than wild type mice; with a higher in-
cidence of carcinogen-induced tumors, accelerated tumor growth rate,
and increased experimental metastasis [30]. Despite these observations,
over-expression of CD155 by tumors has been associated with dimin-
ished activity of tumor-infiltrating lymphocytes and worse prognosis in
several cancer types [31–33] which argues, at least in these tumor
types, against the aforementioned hypothesis and suggests that the
overall effect of CD155 in the TME is in fact immunosuppressive for
many solid tumor indications.
In tumor tissue, the activities of T and NK cells are commonly
suppressed by interactions between checkpoint receptors and check-
point ligands expressed in the TME. Among these are the T cell

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Fig. 2. Upregulation of TIGIT and CD96 diminishes DNAM-1 stimulation of tumor-infiltrating lymphocytes. (A) In tumor associated stroma, activated CD8+ T cells
are likely to express DNAM-1 and comparatively lower levels of TIGIT and CD96 due to lower TCR signaling resulting in a net positive signal generated from CD155
expressed in the stroma. (B) As tumors emerge from tumor-associated stroma into tumor tissue (parenchyma), DNAM-1 can be down-regulated, and the expression of
PD-1, CD96, and likely TIGIT can increase resulting in a net negative signal to the T cell from tumor CD155. Their interactions with CD155 expressed by tumor and
tumor-associated myeloid cells (APCs) are associated with a dysfunctional T cell phenotype.

immunoreceptor with Ig and ITIM domains (TIGIT) and CD96 immune
checkpoint receptors which both compete with DNAM-1 to bind with
CD155 (Fig. 1B) [34]. This competition functions to suppress DNAM-1-
mediated T- and NK cell-activation. These interactions occur with dif-
ferent affinities [35]. For example, DNAM-1 has the lowest affinity for
binding CD155, followed by CD96 which has an intermediate affinity,
and TIGIT which binds with high affinity to CD155 [35,36]. This is
likely due to the unique structural interactions that each of CD96,
TIGIT, and DNAM-1 have with CD155 [35,36]. The competitive inter-
actions between CD96 and TIGIT with DNAM-1 are reminiscent of the
process by which the CTLA4 checkpoint receptor, competes with the co-
stimulatory receptor CD28 for binding to B7 molecules expressed on
antigen presenting cells (APCs) (Fig. 1B) [34,37]. DNAM-1 contains an
intracellular immunoreceptor tyrosine tail (ITT)-like motif, upon in-
teractions with CD155 or CD112, this intracellular domain has been
proposed to signal via the adaptor protein Grb2 [38]. As is the case for
other co-stimulatory molecules including CD28, DNAM-1 down-reg-
ulation has been seen on T cells in the setting of chronic infection
[39,40], and on NK cells in advanced cancers and has been associated
with T cell exhaustion and diminished NK cell-mediated cytotoxicity
[28,29,41,42]. These findings might suggest that loss of co-stimulation
is a key feature of lymphocyte dysfunction, however, the mechanism(s)
underlying this effect is poorly understood [43].
In contrast to DNAM-1 downregulation, TIGIT is highly upregulated
on both CD8+ T cells and tumor-infiltrating regulatory T cells, and has
also been reported on tumor-infiltrating NK cells [44]. The intracellular
domain of TIGIT contains an intracellular immunoreceptor tyrosine-
based inhibitory motif that is responsible for mediating its inhibitory
signaling [45]. Single cell RNAseq analysis of human cancers has re-
vealed co-expression of TIGIT among tumor-infiltrating CD8+ T cells
expressing other checkpoint receptors such as TIM-3, LAG-3, CTLA-4,
and PD-1 [46,47]. This was also shown in a recent series of articles
defining the transcriptional regulation of CD8+ T cell exhaustion in
both chronic viral infection and cancer [48–50]. Importantly, these
effects might be cell type-dependent as expression of TIGIT appears to
be important for the suppressive activity of Tregs in the tumor micro-
environment. Tregs in TIGIT−/− mice have reduced suppressive ac-
tivity, and in mice TIGIT+ Tregs have increased suppression of Th1 and
Th17 immune responses when compared to TIGIT- Tregs [51,52]. Im-
proved CD8+ T cell function has been seen following blockade of TIGIT
alone or in combination with other immunotherapies [53–55].
Similar to TIGIT, upregulation of CD96 expression on intratumor T
and NK cells has been shown in several solid cancer types. Recent
studies primarily in mouse tumor models have indicated a role for CD96
as a T and NK cell checkpoint receptor. Initial investigations suggested
that CD96 mediated human NK cell adhesion to CD155-expressing
target cells [56]. The first evidence that CD96 might act in an inhibitory
capacity was shown in CD96−/− mice, where NK cells were found to
produce greater IFNγ in response to IL12, IL18, or LPS stimulation [57].
It was also shown that these mice were resistant to experimental lung
metastases and carcinogen-induced tumor development [57]. More
recently, CD96 has been shown to reduce the activity of CD8+ T cells,

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Fig. 3. Expression distribution and mutation frequency of CD155 across human cancers.
(A) Expression of CD155 detected by RNAseq across 32 cancer types. Each dot represents a single case, the color of the data point corresponds to whether and what
type of gene alteration is associated with CD155 in each case as described in the legend. Error bars represent SD. (B) As a percentage of total cases, the proportion of
each tumor type that contain a mutation, fusion, amplification, deep deletion, or multiple alterations in the PVR gene. Data presented are publicly available from the
TCGA and interpreted using https://www.cbioportal.org/.

and promote their acquisition of a dysfunctional phenotype in mouse
tumor models [57–59]. Expression of CD96 appears to be most common
among tumor-infiltrating CD8+ T cells and NK cells [44,58,60]. Unlike
TIGIT, expression of CD96 is much less common among CD4+ T cells in
mouse tumor models. In human colorectal carcinoma, expression of PD-
1 and CD96 appears to be selectively upregulated by CD8+ T cells in-
filtrating tumor tissue, but not those in tumor-associated stroma, sug-
gesting that its expression is regulated by antigen exposure or other
factors in the tumor microenvironment [58]. Despite these observa-
tions, further studies will need to establish whether the im-
munosuppressive activity of CD96 seen in mice is conserved in humans.
In summary, the effect that CD155 has on tumor immune suppression
will depend on the relative balance of stimulatory (DNAM-1) and in-
hibitory (TIGIT and CD96) signals produced by these receptors in
tumor-infiltrating T and NK cells. In addition to DNAM-1, TIGIT, and
CD96, a recent study utilizing a novel method for ligand-receptor

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proteomics identified that the NK cell receptor KIR2DL5 is also likely to
be a ligand for CD155, however, the significance of this interaction has
not yet been defined [61]. In tumors, an increase in expression of the
inhibitory receptors (TIGIT and CD96) and reduced expression of co-
stimulatory receptors (DNAM-1), is likely responsible for the observed
immunosuppressive properties of CD155 seen in solid tumors (Fig. 2A
and B).
4. Expression and function of CD155 on host immune cells
Under physiological conditions, CD155 is widely expressed at low
levels on immune cells where it has been proposed to play various roles
such as co-stimulation of CD4+ T cells [62] and MHC-independent
positive-selection of T cells in the thymus [63]. There is also evidence
that CD155 is expressed on endothelial cells where it has been shown to
attenuate CD8+ T cell responses [64]. Recent evidence indicates that
CD155-expression can be modulated on tumor-infiltrating leukocytes
and that this might function in suppressing the activity of anti-tumor
immune responses [9]. To date the most compelling evidence sup-
porting its role in immune suppression came from studies in gene-
modified mice deficient in CD155 expression. In these mice significant
delays in primary tumor growth and experimental metastasis were seen
in comparison to wild-type (CD155-expressing) mice [9]. Bone marrow
chimera studies were used to confirm that CD155-expressing haema-
topoietic cells were responsible for suppression of T and NK cell-
mediated anti-tumor immune responses [9].
CD155 expression on immune cells can be detected among tumor-
infiltrating leukocytes in the primary tumor and tumor-draining lymph
nodes, however, it appears to be mostly restricted to myeloid cells [9].
In human melanoma samples, CD155 expression has been observed on
CD14+CD11c− macrophages, CD14+CD11c+ myeloid cells, and
CD14−CD11c+ dendritic cells (DCs). Co-localization of CD155-ex-
pressing myeloid cells with an M2-like, immunosuppressive phenotype
with T cells in these tumors suggested a potentially immunosuppressive
role [9].
The mechanism(s) responsible for upregulation of CD155 on tumor-
infiltrating myeloid cells is currently unclear. One report in patients
with sepsis revealed that CD155 and the closely related CD112 (Nectin-
1) molecules were selectively upregulated by circulating monocytes
[65]. In a separate study, ex vivo exposure of mouse bone marrow-de-
rived macrophages and B cells to LPS was shown to promote upregu-
lation of CD155 in an NF-κB-dependent manner [66–68]. Given that
toll-like receptor (TLR) ligands are common in the blood of both septic
patients and in the tumor microenvironment, this is a possible stimulus
for myeloid cell CD155 upregulation, however, this hypothesis requires
testing.
5. Expression of CD155 in human cancers
While expression of CD155 by tumor-infiltrating myeloid cells has
been shown to play a significant role in suppressing the anti-tumor
immune response [9], in the TME the primary source of CD155 is
probably tumor cells [8]. Overexpression of CD155 by tumor cells was
first seen in the early 1990s by researchers attempting to develop
therapeutic monoclonal antibodies against proteins overexpressed by
tumor cells, however, at the time it was not recognized that the tumor
antigen targeted was in fact CD155 [8,69]. Overexpression of CD155
has since been reported in many cancers including melanoma [70],
lung adenocarcinoma [71], pancreatic cancer [31], ovarian cancer
[41], myeloid leukemia [28], neuroblastoma [28,69], colorectal cancer
[72], cholangiocarcinoma among others (Fig. 3A) [73]. This observa-
tion has been associated with poor clinical measures including lymph
node metastasis, a reduction in tumor-infiltrating lymphocytes, tumor
histological grade, primary tumor size, and poor prognosis in retro-
spective studies across various solid cancer types [31,73,74]. To better
understand the relationship between CD155 and clinical correlates,
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Seminars in Cancer Biology 65 (2020) 189–196
several ongoing clinical trials investigating various treatments are at-
tempting to measure CD155 expression in tumor tissue prior, or fol-
lowing the initiation of treatment in advanced solid tumors (Clin-
Trials.gov: NCT03667716), ovarian and gastric cancers, (ClinTrials.gov:
NCT03342417), melanoma (ClinTrials.gov: NCT03712358), bladder
cancer (ClinTrials.gov: NCT03789682), and prostate cancer (Clin-
Trials.gov: NCT03071328). Importantly, elevated soluble CD155 has
been associated with increased tumor burden, and has been proposed as
a potential biomarker of disease progression [18,75].
Several findings suggest that CD155 is associated with tumor pro-
gression: First, genetic deletion of CD155 from tumor cells in mice re-
sults in a significant delay in tumor growth and metastasis [9,76].
Second, expression of CD155 in transplantable tumor models in mice
genetically deficient in CD155 was found to significantly enhance pri-
mary tumor growth and metastasis [9,76]. While overexpression of
CD155 might support tumor progression due to its cell-intrinsic effects,
recent evidence suggests tumor cell expression of CD155 meaningfully
suppresses anti-tumor immune responses. Relating to the latter ob-
servation, using several retrospective cohorts in melanoma, a strong
and significant association between poor response to cancer im-
munotherapy (either anti-PD-1 alone, or in combination with anti-
CTLA4) was identified in melanoma [77]. This followed the demon-
stration that elevated CD155 expression associated with a diminished
IFNγ gene-expression signature, but not necessarily reduced CD8+ T
cell infiltration in pre-immunotherapy-treated tumor samples and this
specifically highlighted CD155 and associated pathway members as key
regulators of CD8+ T cell function and response to cancer im-
munotherapy [77]. Together, these studies suggest that CD155 over-
expression by tumor cells plays an important role in promoting tumor
progression both as a result of intrinsic oncogenic pathway activation,
and also of extrinsic suppression of anti-tumor immune responses. Im-
portantly, it is not yet understood whether soluble CD155 contributes to
immune suppression in the tumor microenvironment, however, if the
soluble CD155 isoforms can bind CD96 and TIGIT, this might be a
possibility.
The overexpression of CD155 observed in cancers likely occurs as a
result of a variety of mechanisms. CD155 overexpression has been as-
sociated with the cellular stress responses to reactive oxygen species
(ROS), and also constitutive expression of the MYC oncogene with in-
duction of the ATM-ATR DNA damage repair pathway in human tumor
cell lines [78–82]. In addition, a single study found that in vitro cultures
of human melanoma cells upregulated CD155 when exposed to IFNγ
similar to the adaptive upregulation of PD-L1, however this observation
has not been replicated [66,83]. For PD-L1, its expression in tumors
tends to be limited to regions of immune cell infiltration [84,85], except
for rare instances in which PD-L1 is constitutively expressed by tumor
cells [86]. By contrast, when expressed, CD155 staining tends to be
homogenous throughout tumor tissue, independent of immune cell lo-
calization [87]. This observation lends itself to a genetic rather than an
external immunological cause as seen with PD-L1 upregulation in the
presence of IFNγ. One likely mechanism is amplification of the PVR
gene itself which appears to be most common in uterine carcinoma (∼7
% of cases) and associates with its relatively high expression of CD155
(Fig. 3A and B). However, in tumors which show low CD155 expression
and do not show evidence for amplification or copy number gain such
as AML, DLBC, and Thymoma, selection against CD155 overexpression
may be driven by DNAM-1 expression on tumor infiltrating lympho-
cytes; however, for this to occur stimulatory signaling via DNAM-1
would have to outweigh immunosuppressive signals from TIGIT and
CD96. Nevertheless, these CD155 low cancers seem to be an exception;
the majority of tumors types show high levels of CD155 gene expression
(Fig. 3A and B). In addition to amplification of the PVR gene, mutations
in other genes that result in enhanced Ras-Raf-MEK-ERK activation,
elevated fibroblast growth factor signaling [7,88], and also aberrant
activation of the hedgehog signaling pathway have been shown to re-
sult in CD155 overexpression in vitro [89]. An understanding of the
J.S. O’Donnell, et al.
mechanisms responsible for CD155 overexpression by tumor cells may
allow for the development of therapies to decrease its expression and
enhance sensitivity to cancer immunotherapies.
6. Targeting the CD155 axis with therapies
The significant immune suppression induced by CD155 in addition
to its very broad expression distribution in cancer highlights it potential
as a therapeutic target. Supporting this idea, preclinical studies in mice
genetically deficient in either CD155 or of TIGIT and CD96 have en-
hanced anti-tumor immunity [9,90]. As such, blocking this interaction
with CD155 in the TME might be an effective therapy for tumor control.
In experimental settings, the use of monoclonal antibodies against
CD155 has been explored as a method for improving tumor control. In
one study, experimental metastatic burden was reduced in im-
munocompetent mice following administration of anti-CD155 [91]. in
vitro assays revealed that anti-CD155 treatment reduced tumor cell
migration and invasion [91]. Additionally, CD155 blockade has also
been shown to improve the function of antigen presenting cells in ex-
perimental sepsis [92]. To date, clinical studies have not been carried
out to assess whether CD155 blockade is feasible in human cancers. One
potential limitation of this approach could be that in addition to
blocking the interactions of CD155 with TIGIT and CD96, CD155
blockade might impact stimulatory interactions between DNAM-1 and
CD155 (Fig. 1B). Selection of cancer indications for clinical trials tar-
geting CD155 should therefore be guided by CD155 expression levels on
tumor cells as well as TIGIT/CD96 and DNAM-1 expression levels on
infiltrating lymphocytes.
To avoid any issue inherent in blocking CD155-DNAM-1 interac-
tions, targeting exclusively the inhibitory side of CD155 pathway (CD96
and TIGIT) has already been shown to have a beneficial effect on tumor
control (Fig. 4). Early studies suggested that TIGIT blockade enhances
the in vitro killing of tumor cells by mouse PBMCs [93]. In addition to
this, blockade of CD96 has demonstrated efficacy in treatment of
Fig. 4. Progression of therapies targeting the CD155 axis in cancer.
A description of the current phase of development that therapies targeting CD155 or its ligands, DNAM-1, TIGIT, and CD96.
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Seminars in Cancer Biology 65 (2020) 189–196
experimental metastasis models including B16F10, 3 L L lung carci-
noma, LWT1 melanoma, and RM-1 prostate carcinoma through an
IFNγ- and NK cell-dependent mechanism [60]. More recently, blockade
of CD96 has also been shown to improve CD8 T cell-mediated anti-
tumor responses in mice [58].
Blockade of TIGIT and CD96 together or in combination with other
conventional checkpoint inhibitors blocking PD-1 or CTLA4 appears to
be more effective than monotherapy treatment. Importantly, this has
been shown in models of experimental metastasis (in which tumor
control is NK cell-mediated) [60,94], primary tumor growth models
(usually CD8+ T cell-mediated) [9,58], and also spontaneous metas-
tasis studies following surgery to remove the primary tumor (NK cell
and T cell-mediated) [94]. However, whether the anti-tumor effect of
targeting CD96 and/or TIGIT partly or entirely depends on blocking
CD96/CD155 versus TIGIT/CD155 interaction and whether redundancy
exists between CD96 and TIGIT is still unclear [94]. These findings
provide evidence to suggest that independent of inhibitory receptor
competition for DNAM-1, CD96 and TIGIT have intrinsic im-
munosuppressive signaling effects. Mechanistic studies to investigate
the differential regulation and impact that CD155, DNAM-1, CD96, and
TIGIT have on the anti-tumor immune response are needed. An addi-
tional consideration for the therapeutic blockade of TIGIT and CD96 is
that their upregulation has been associated in tumor-infiltrating T cells
with terminal differentiation. In turn, this might suggest that blocking
the interactions of TIGIT/CD96 with CD155 might do little to re-
invigorate the anti-tumor immune response [48–50], however, the fact
that therapeutic efficacy has been seen preclinically argues against this.
There are currently several clinical trials in various phases testing the
efficacy of anti-TIGIT monoclonal antibodies. To date, there are no
clinical trials assessing the efficacy of anti-CD96 therapy (Fig. 4).
In addition to CD155 checkpoint blockade, another therapeutic
approach takes advantage of the overexpression of CD155 by tumors.
An oncolytic viral therapy, Poliovirus-Rhinovirus Chimera (PVSRIPO)
which binds specifically to CD155 has been developed to promote
J.S. O’Donnell, et al.
immunogenic tumor cell death, inducing lysis of tumor cells and the
release of Danger-Associated Molecular Patterns (DAMPs) capable of
inducing an anti-tumor immune responses involving T and NK cells
[95–98]. Also, CD155-expressing dendritic cells and macrophages when
exposed to PVSRIPO where shown to engage T cells and limit viral
replication [96]. PVSRIPO is now undergoing clinical testing at various
phases (Fig. 4).
7. Perspectives
The findings discussed throughout this review have highlighted
some interesting questions that will allow for a more complete under-
standing of the roles that CD155 plays in the tumor microenvironment
and how best to target this axis. First, it will be important to more fully
define the tumor cell-intrinsic and -extrinsic effects of CD155. Second,
we need to understand how CD155 expression is regulated by tumor
cells and by myeloid cells in the tumor microenvironment, as these
processes might be targetable and understanding will be required to
overcome potential issues with blocking CD155 expressed in healthy
tissues. Third, it would be helpful to understand how TIGIT, CD96, and
DNAM-1 are differentially regulated and functionally interact in the
tumor microenvironment and whether this mechanism differs between
different lymphocyte subsets and across different cancer types. Fourth,
it would be helpful to understand what effect soluble CD155 has on the
efficacy of cancer immunotherapy. Can soluble CD155 suppress lym-
phocyte function in the same way that membrane-bound CD155 does?
Finally, clinical trials to assess the feasibility and efficacy of blocking
CD155 interactions with TIGIT and CD96 are required. Are there par-
ticular tumor types and therapeutic combinations for which greater
efficacy will be seen? Answering these questions will help guide clinical
trials and allow for the development of more effective therapies tar-
geting the CD155 axis in cancer.
Declaration of Competing Interest
M. J. Smyth has research agreements with Bristol Myers Squibb and
Tizona Therapeutics and is on the Scientific Advisory Board at Tizona
Therapeutics and Compass Therapeutics. X.Y. Li, J.S. O’Donnell, and J.
Madore declare no conflict of interest.
Acknowledgments
The project was funded by a National Health and Medical Research
Council of Australia (NH&MRC) Program Grant (1132519) and Project
Grant (1098960). M. J. S. was supported by a Senior Principal Research
Fellowship (1078671). The authors thank Dr. Robert Johnston (Bristol
Myers Squibb) for critical reading of this manuscript.
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