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CHECKPOINT BLOCKADE
Bidirectional signals of PD-L1 in T cells that
fraternize with cancer cells
PD-L1 expressed by T cells provides backward and forward signals to restrain both innate and adaptive immune
responses in tumor tissues.
Rachel M. Gibbons Johnson, Ti Wen and Haidong Dong
S
ince the discovery of the role of
tumor-associated PD-L1 (also named
B7-H1) in tumor immune evasion1,
blockade of PD-L1 or its receptor PD-1 has
become a standard of care in several human
cancers. However, other cellular sources
of PD-L1 and the role of PD-L1 in the
interactions between immune cells in tumor
environments have not been completely
defined. In this issue of Nature Immunology,
Diskin et al.2 identify tumor-infiltrating
T cells as another cellular source of PD-L1
in tumor tissues. They found that PD-L1
provides bidirectional signals, which restrain
both adaptive and innate antitumor immune
responses, especially in a pancreatic cancer
model. Thus, T cell–associated PD-L1 may
become a new therapeutic target of cancer
immunotherapy.
The original cloning of human PD-L1
from human placenta3, an immune-
privileged organ in the human reproductive
system, implies a role for PD-L1 in the
protection of growing organs or tissues
from unwanted immune attack. In line
with this expectation, growing tumor cells
take advantage of PD-L1 overexpression
to evade immune attack, especially at the
interface between tumor cells and immune
cells1. PD-L1 allows tumor cells to evade
immune attack by binding with PD-1 or
CD80, two receptors for PD-L1 expressed
by effector T cells, to dampen the antitumor
activity of immune cells in tumor tissues4.
Although tumor-associated PD-L1 seems to
be a major therapeutic target for restoring
the antitumor function of immune cells in
tumor tissues, PD-L1 blockade therapy also
achieved significant therapeutic effects in
patients with lower tumor expression of
PD-L1 but higher immune cell expression
of PD-L15. This paradox challenges the
original conception of tumor-associated
PD-L1 as a major therapeutic target of
cancer immunotherapy and highlights the
role of PD-L1 expressed by immune cells
in response to cancer immunotherapy. The
functions of PD-L1 expressed by immune
Nature Immunology | www.nature.com/natureimmunology
Backward signaling Forward signaling
Tumor cells
T helper function
TH1
PD-L1 PD-1
M1
TH17 M2
CD4+ T cell Macrophage
GzmB ↓
T-bet ↓
TNF ↓
IFN-γ ↓
T effector function
CD8+ T cell CTL
Fig. 1 | Bidirectional signaling of PD-L1 expressed by T cells in tumor tissues. The backward signaling
of PD-L1 (PD-1→PD-L1) changes the cell fate of CD4+ T cells from an antitumor subset (TH1) to a
protumor subset (TH17) and limits the ability of CD8+ T cells to gain effector functions. The forward
signaling of PD-L1 (PD-L1→PD-1) changes antitumor macrophages (M1 type) to protumor macrophages
(M2 type) and dampens effector T cells’ antitumor activities by suppressing inflammatory cytokine
(tumor necrosis factor (TNF) and interferon (IFN)-γ) and cytotoxic effector molecule (granzyme B
(GzmB)) production at tumor sites. Collectively, the bidirectional signaling of PD-L1 expressed by tumor-
infiltrating T cells converges to restrain a network of immune cells that are needed to mount an effective
antitumor immune response. CTL, cytotoxic T lymphocyte.
cells are important to understand because some conceptual challenges. For example, as
physicians need to know whether PD-1 or most activated T cells already express PD-1,
PD-L1 blockade therapy will benefit patients it is not clear whether PD-L1 expressed
if their tumor cells do not express high levels by the same T cells would function as a
of PD-L1 but their immune cells do. Some ligand or receptor. On the other hand, if
preclinical studies addressed this question PD-1 signals are sufficient to dampen T cell
and found that PD-L1 expressed by host function, why do T cells need to express
cells (mainly myeloid cells), rather than PD-L1? To that end, Diskin et al. propose
tumor cells, may be key in responses a new mechanism of function for PD-L1
to PD-1 or PD-L1 blockade therapy6. expressed by tumor-infiltrating T cells:
However, the role of PD-L1 expressed by PD-L1 may function as both a ligand and a
tumor-infiltrating T cells has not yet been receptor to transmit forward and backward
clearly defined. signals to regulate immune responses in
In addressing the role of PD-L1 expressed tumor tissues. The authors first revealed that
by tumor-infiltrating T cells, we are facing T cell expression of PD-L1 is a consequence
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of T cell responses to tumor environment
cues. As tumor cells grow rapidly, some
tumor cells die due to insufficient oxygen
and nutrition. The dead tumor cells release
tumor antigens and inflammatory factors
that can attract immune cells to attack
the tumor. However, the tumor antigens
and inflammatory cytokines can activate
the expression of PD-L1 in T cells that
enter tumor tissues, as reported by Diskin
et al. This phenomenon is striking in
pancreatic cancers where tumor cells did not
express PD-L1, but the tumor-infiltrating
T cells expressed more PD-L12. Second,
they addressed the immune-suppressive
function of PD-L1 expressed by T cells
in tumor tissues, using an elegant model
in which T cell expression of PD-L1 can
be conditionally depleted within tumor
tissues. They found that PD-L1 expressed by
T cells transduces bidirectional signals that
converge to suppress a network of immune
cells in tumors. In the back-signaling mode,
PD-L1 functions as a receptor to transmit
signals back into T cells once PD-L1 is
engaged with its natural binding partner
PD-1. (It is not clear whether CD80, which
can also can bind PD-L1, would initiate
the same back-signaling through PD-L1.)
These backward signals from PD-L1 into
T cells not only limit the differentiation of
CD4+ T cells into T helper cells (TH1 cells),
which promote antitumor immunity, but
also foster the conversion of CD4+ T cells to
inflammatory T cells (TH17), which promote
tumor growth. In addition, the back-signals
from PD-L1 prevent CD8+ T cells from
gaining cytotoxic effector functions. Of
note, the back-signaling function of PD-L1
expressed by T cells seems to distinguish
PD-L1-positive T cells from traditional
regulatory T cells (Treg cells), which mainly
use PD-1 to receive signals from PD-L17.
But more work needs to be done to clearly
separate immunosuppressive functions
of Treg cells from those of PD-L1-positive
T cells. In the forward-signaling mode,
PD-L1 functions as a ligand to engage PD-1
expressed by other T cells or macrophages.
In particular, the PD-L1→PD-1 pathway,
but not the PD-L1→CD80 pathway, can
reprogram macrophages to become more
immunosuppressive (M2 type) and promote
tumor growth rather than inhibit it, in
contrast to the normal antitumor function
of macrophages (M1 type). In this regard,
PD-L1 expressed by T cells provides a
new platform of T cell–T cell and T cell–
macrophage crosstalk via PD-1 and leads to
a spectrum of suppressive signals in tumor
tissues (Fig. 1). From there, PD-L1 expressed
by T cells emerges as a new biomarker for
PD-1 or PD-L1 blockade therapy, especially
for cancers with few tumor cells that
express PD-L1. Future studies are needed
to determine whether there is a correlation
between T cell–associated PD-L1 and the
prognosis of cancer progression or
responses to PD-1 or PD-L1 blockade
therapy. Its clinical implication for
pancreatic cancer is strong, as predicted by
Diskin and colleagues.
Given the key role of PD-L1 in the
crosstalk among immune cells and tumor
cells, targeting PD-L1 signaling between
immune cells should become another
therapeutic goal, along with targeting
PD-L1 signals in tumor cells. However,
PD-L1-targeting inhibitors should be
used with caution. As T cells can also be
considered a growing population after
activation, it is not surprising that they will
need PD-L1 to protect themselves as well.
It has been reported that PD-L1 is needed
by T cells to prevent fratricide during the
contraction phase8, in order to maintain
a pool of effector T cells. Historically, the
presence of autoantibodies to PD-L1 in
patients with arthritis has been associated
with T cell loss9.
Besides its bidirectional signaling
function that can be triggered by ligation
with PD-1 or CD80, PD-L1 may have a
T cell–intrinsic function that promotes
T cell survival. It has been reported
that PD-L1-deficient CD8+ T cells have
reduced expression of Bcl-xL, a pro-survival
molecule, along with compromised
Nature Immunology | www.nature.com/natureimmunology
function8,10. Although the link between
PD-L1 and Bcl-xL expression has not
been defined, PD-L1 inhibitors should be
used with caution to avoid disrupting the
T cell–intrinsic functions of PD-L1. In this
regard, an ideal therapeutic PD-L1 antibody
should be able to block PD-L1’s forward
and backward signaling but not disrupt
PD-L1’s intrinsic functions in T cells. More
studies are warranted to better understand
the intrinsic functions of PD-L1 in T cells as
well, such as the recently characterized roles
of PD-L1 as an RNA-binding protein and
as a driver of metabolism in human cancer
cells11,12. There is no doubt that our efforts
in seeking a deep understanding of PD-L1
biology will eventually pay off in benefits
to patients once we find an optimal way to
restrain the tumor-promoting functions of
PD-L1 without compromising existing
T cell function. ❐
Rachel M. Gibbons Johnson1, Ti Wen2 and
Haidong Dong   2 ✉
1
Biology Discipline, University of Minnesota Morris,
Morris, MN, USA. 2Departments of Urology and
Immunology, Mayo Clinic College of Medicine and
Science, Rochester, MN, USA.
✉e-mail: dong.haidong@mayo.edu
Published: xx xx xxxx
https://doi.org/10.1038/s41590-020-0599-3
References
1. Dong, H. & Chen, L. J. Mol. Med. 81, 281–287 (2003).
2. Diskin. B. et al. Nat. Immunol. https://doi.org/10.1038/s41590-
020-0620-x (2020).
3. Dong, H., Zhu, G., Tamada, K. & Chen, L. Nat. Med. 5,
1365–1369 (1999).
4. Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. Annu. Rev.
Immunol. 26, 677–704 (2008).
5. Herbst, R. S. et al. Nature 515, 563–567 (2014).
6. Tang, H. et al. J. Clin. Invest. 128, 580–588 (2018).
7. Kamada, T. et al. Proc. Natl Acad. Sci. USA 116, 9999–10008
(2019).
8. Pulko, V. et al. J. Immunol. 187, 5606–5614 (2011).
9. Dong, H. et al. J. Clin. Invest. 111, 363–370 (2003).
10. Saha, A. et al. J. Clin. Invest. 126, 2642–2660 (2016).
11. Tu, X. et al. Mol. Cell 74, 1215–1226.e4 (2019).
12. Chang, C. H. et al. Cell 162, 1229–1241 (2015).
Competing interests
The authors declare no competing interests.