For Immunopathol Dis Therap. Author manuscript; available in PMC 2017 Mar 8.
Published in final edited form as:
PMCID: PMC5341794
NIHMSID: NIHMS845622
Reinvigorating Exhausted T Cells by Blockade of the PD-1
Pathway
Emory Vaccine Center and Department of Microbiology and Immunology,
Emory University School of Medicine, Atlanta, GA 30322
*Address all correspondence to: Rafi Ahmed, Ph.D,
Emory Vaccine Center and Department of Microbiology and Immunology, Emory
University School of Medicine, Atlanta, GA 30322; Tel.:404-727-4700;
Fax:404-727-3722;
ude.yrome@demhar Abstract
T-cell exhaustion due to persistent antigen stimulation is a key feature
of chronic viral infections and cancer. Programmed cell death-1 (PD-1) is a
major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores
T-cell function and improves pathogen control and tumor eradication.
Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated
significant antitumor activity. Recently, antibodies blocking PD-1 have been
approved for use in cancer patients. In this review, we summarize the role of
the PD-1 pathway in chronic infection and cancer and the therapeutic potential
of PD-1-directed immunotherapy in patients with chronic infection or cancer.
Keywords: cancer, chronic infection, immunotherapy, programmed cell death-1, T-cell exhaustion
I. PERSPECTIVES
Memory T cells are generated when acute infections are cleared by the immune
system. These cells rapidly reactivate effector functions upon antigen re-encounter
and persist long term via homeostatic proliferation, independently of
antigen.1, 2 These key properties of memory T cells allow them to
provide long-term protective immunity. In contrast, chronic infections where the
virus persists result in exhaustion of the T cells, which are then unable to bring
the infection under control.
Prolonged antigen stimulation and inflammation lead to loss of effector
functions of virus-specific CD8 T cells in a progressive and hierarchical manner,
even resulting in clonal deletion.3,
4 This process, originally found
in chronic viral infections, was termed T-cell exhaustion and has since been
demonstrated to be a common feature of many chronic infections and cancer.1, 5 Exhausted T cells, characterized by defects in effector
functions and elevated and sustained expression of inhibitory receptors, are
distinctly different from functional effector or memory cells.6, 7 Although complex immunosuppressive mechanisms, including both
intrinsic and extrinsic factors, can contribute to the establishment and maintenance
of the persistent infection and T-cell dysfunction, PD-1 (CD279),8 an inhibitory receptor of CD28
family, is well known to play a major role in regulating T-cell exhaustion. In this
review, we summarize the role of the PD-1 pathway in regulating T-cell exhaustion in
chronic infection and cancer and discuss the therapeutic potential of PD-1-directed
immunotherapy to treat patients who are chronically infected or have cancer.
II. THE ROLE OF THE PD-1 PATHWAY IN T-CELL EXHAUSTION
PD-1 is expressed in various hematopoietic cells including T cells, B cells,
natural killer (NK) cells, NK T (NKT) cells, monocytes, macrophages, and dendritic
cells (DCs) following their activation.9 PD-1 binds to its two ligands: programmed cell death 1 ligand-1
(PD-L1; B7-H1; CD274)10, 11 and PD-L2 (B7-DC;
CD273),12, 13 both of which are B7 family members. PD-L1 is
constitutively expressed in a wide range of cells including hematopoietic and
nonhematopoietic cells. In contrast, PD-L2 expression is restricted to professional
antigen presenting cells (APCs; monocytes, macrophages, and DCs) and a certain
subset of B cells. Inflammatory cytokines such as interferons (IFNs; α,
β, and γ) are potent regulators of both PD-L1 and PD-L2
expression.9, 14 The function of PD-1 is best
characterized in T cells. Its expression is induced by activation-driven T-cell
receptor (TCR) signaling and further up-regulated by cytokines.14 Upon engagement of PD-1 with its
ligands, the SH2-domain containing tyrosine phosphatase 1 (SHP-1) and SHP-2 are
recruited to the phosphorylated immunoreceptor tyrosine-based switch motif (ITSM) in
the cytoplasmic domain of PD-1. Recruitment of SHP-1 and SHP-2 inactivates proximal
effector molecules such as ZAP70 and phosphatidylinositol-3-kinase (PI3K),
attenuating TCR- and CD28-mediated signaling ().15–17
PD-1 signaling. PD-1 contains two tyrosine-based signaling motifs in the
cytoplasmic domain: an immunoreceptor tyrosine-based inhibitory motif (ITIM)
and an ITSM. Upon engagement by PD-L1 or PD-L2, PD-1 is phosphorylated at both
tyrosine residues. Phosphorylated ITSM recruits SHP-1 and SHP-2 that
dephosphorylate effector molecules such as ZAP70 and PI3K activated by TCR and
CD28 signaling. As a result, PD-1 signaling inhibits T-cell proliferation,
survival, cytokine production, protein synthesis, and glucose metabolism.
Our previous finding that PD-L1 has a differential role in hematopoietic
cells and nonhematopoietic cells in regulating the T-cell response suggests a model
for which PD-1/PD-1 ligand (PD-L) interaction operates.18 In chronic LCMV infection, PD-L1 deficiency in
hematopoietic cells enhanced the T-cell response in terms of both magnitude and
function. In comparison, PD-L1 deficiency in nonhematopoietic cells had no effect on
the T-cell response but resulted in better virus control. This indicates that the
PD-1 pathway restrains T cells from killing virus-infected cells as well as
attenuating T-cell activation. The PD-1/PD-L1 interaction between T cells and
infected cells (or cancer cells) inhibits target cell elimination by T cells.
Abrogating this interaction releases the brake on T cells and promotes their
effector functions, killing of target cells (). Therefore, the PD-1 pathway negatively regulates T cells during
priming and also the effector phase when T cells act on the target cells. This
presumably results in more profound “rescue” effects by the blockade
of PD-1 than do other inhibitory receptor blockades.
Blockade of PD-1/PD-L1 interactions between CD8 T cells and target
cells. Antibody-mediated blockade of the PD-1 pathway promotes T cell-mediated
elimination of target cells.
The immunoregulatory roles of PD-1 are responsible for limiting excessive
T-cell activation to prevent immune-mediated tissue damage. However, prolonged TCR
stimulation and PD-1 expression lead to T-cell dysfunction, and pathogens or cancer
cells exploit the PD-1 pathway to persist and resist immune response. Therefore, the
PD-1 pathway is an important determinant of the outcome of the T-cell response,
regulating the balance between effective host defense and immunopathology,
implicating the potential for manipulating the PD-1 pathway against various human
diseases.
During chronic infection and cancer, expression of both PD-1 and PD-1 ligands
is abundant; continuous antigen stimulation maintains high levels of PD-1 expression
on antigen-specific T cells and the expression of PD-1 ligands is also up-regulated
by inflammatory stimulation. PD-1–mediated T-cell dysfunction strongly
dampens antiviral or antitumor immune response. The effect of interfering with the
PD-1 pathway on the restoration of T-cell function has been shown in many animal
models and human diseases. Recently, clinical trials targeting the PD-1 pathway have
revealed very promising results. Many preclinical studies of PD-1 pathway blockade
in chronic viral infections and clinical trials in many different cancers are
currently ongoing.
III. THE THERAPEUTIC POTENTIAL OF INHIBITING PD-1 SIGNALING IN CHRONIC VIRAL
INFECTION
The dominant role of PD-1 in regulating T-cell exhaustion was first described
by our group in a mouse model of chronic LCMV infection. In this model, we found
that exhausted CD8 T cells had increased PD-1 expression. Furthermore, blockade of
the PD-1 pathway restored effector functions of LCMV-specific CD8 T cells and
significantly reduced viral load.19 This finding has been further extended to other types of
chronic infections in mice, nonhuman primates, and humans.
In HIV infection, PD-1 expression on HIV-specific CD8 T cells was correlated
with impairment of CD8 T-cell function, high viral load, disease progression, and
reduced CD4 count. In vitro blockade of PD-1 on HIV-specific CD8 and CD4 T cells
enhanced proliferation, cytokine production, and survival.20, 21
Recently, the effect of blocking PD-1/PD-L interactions on HIV disease progression
has been shown in vivo using the humanized mouse model of chronic HIV infection. In
vivo administration of anti-PD-L1 antibody increased both CD4 and CD8 T cells that
could suppress viral replication in HIV-1 chronically infected mice, showing a
reduction in the HIV plasma viral load.22 In addition to HIV, the role of the PD-1 pathway has been
investigated in other chronic viral infections such as HCV. In the initial stage of
HCV infection, most HCV-specific T cells expressed PD-1. In patients that resolve
this disease, PD-1 expression on these cells was reduced, whereas chronically
infected patients maintained a high level of PD-1 expression and HCV-specific CD8 T
cells remained dysfunctional. In vitro blockade of the PD-1 and PD-L interaction
enhanced the proliferation and function of HCV-specific CD8 T cells.23, 24 One recent report demonstrated the impact of interrupting
PD-1 signals in chronically HCV-infected chimpanzees. Following PD-1 blockade, one
of the three animals had significantly reduced HCV viremia that was associated with
restored intrahepatic CD4 and CD8 T-cell response. It has been suggested that
preexisting virus-specific T cells are likely to be essential for the success of
PD-1 blockade therapy in this model.25 Blocking the PD-1 pathway was also found to promote an
antiviral immune response in simian immunodeficiency virus (SIV) infection of rhesus
macaques. Proliferation and polyfunctionality of SIV-specific CD8 T cells were
augmented upon PD-1 blockade, and improved antiviral immunity was followed by viral
load reduction and prolonged survival of chronically infected rhesus
macaques.26 Together,
these preclinical studies show that PD-1 expression on virus-specific T cells is
correlated with their functional defects, and interrupting PD-1 signaling can
reverse this decline. The fact that exhaustion is reversible and not an untreatable
state indicates powerful therapeutic potential for manipulating the PD-1 axis to
reinvigorate dysfunctional T cells in chronic viral infections.
Currently, one clinical trial has been reported on PD-1 blockade in chronic
viral infection. Anti-PD-1 antibody (BMS-936558, a fully human monoclonal antibody
targeting PD-1) was used to treat patients chronically infected with HCV. Following
a single infusion, suppression of HCV replication was observed in 11.1% of
patients (5/45).27 Also in this
trial, one patient who previously did not respond to IFN-α therapy had
undetectable viral load for at least 1 year following administration of the
anti-PD-1 antibody. This promising result warrants further exploration of PD-1
blocking agents for therapeutic use in human chronic viral infection.
IV. THE PD-1 PATHWAY IN ANTITUMOR IMMUNITY AND PD-1-DIRECTED CANCER
IMMUNOTHERAPY
PD-1 and PD-L1 interaction in the tumor environment is a mechanism used by
the tumor to resist destruction by the immune system. PD-L1 is expressed by many
types of cancer cells and up-regulated by various inflammatory stimuli in the tumor
environ-ment.28, 29 Myeloid cells in tumors were shown
to express PD-L1 and mediate inhibition of T cells.30 Tumor-infiltrating T cells express high levels of
PD-1 due to prolonged exposure to the tumor antigen and immunosuppressive
environment and exhibit similar functional and phenotypic properties as the
exhausted T cells in chronic infection. This includes defects in effector cytokine
production and up-regulated expression of inhibitory receptors.31–33 Currently, the prevailing mechanism underlying the
PD-1/PD-L1 axis in tumor sites is that the interaction of PD-L1 on tumor cells with
PD-1 on tumor-infiltrating lymphocytes (TILs) delivers negative signals and inhibits
antitumor T-cell response, facilitating tumorigenesis.
The role of PD-1 in tumor immune evasion was first shown when P815 tumor
cells were transfected with PD-L1 and they became less susceptible to cytotoxic
T-cell-mediated killing. This report also showed that the growth of
PD-L1+ myeloma cells was completely suppressed in syngeneic
PD-1–deficient mice, whereas rapid tumor growth was observed in wild-type
littermates.34 Multiple in
vivo mouse studies have shown that the PD-1/PD-L1 interaction inhibits antitumor
immunity, and abrogating this interaction enhances the T-cell-mediated antitumor
response, leading to tumor regression.29, 34, 35 Encouraging results from preclinical studies and
the therapeutic potential of blocking the PD-1 pathway have led to clinical
development of several blocking antibodies against PD-1 or PD-L1. Currently, the
results of clinical trials targeting the PD-1 pathway are very promising. Blockade
of the PD-1 pathway using either anti-PD-1 or anti-PD-L1 antibodies has revealed
high clinical response rates and was effective in patients with advanced cancer
including metastatic melanoma, non-small cell lung cancer (NSCLC), renal cell cancer
(RCC), bladder cancer, Hodgkin’s lymphoma, head and neck cancer, and breast
cancer36–60 (). Clinical responses tended to be durable and were accompanied
by less adverse effects than those seen with ipilimumab, a CTLA-4 blocking antibody
used for treating metastatic melanoma. Recently, the Food and Drug Administration
(FDA) approved two anti-PD-1 antibodies, pembrolizumab (Merck) and nivolumab
(Bristol-Myers Squibb), for the treatment of unresectable or metastatic
melanoma.
TABLE 1
Published clinical trials targeting PD-1 pathway in cancer patients.
| Cancer types | Sponsor/Company | Target | References |
|---|
| Melanoma | BMS | PD-1 | 38,
40, 42, 43,
44, 49, 51,
60 |
| PD-L1 | 39 |
| Merck | PD-1 | 41,
48 |
| Roche/Genentech | PD-L1 | 45,
61 |
Non small-cell lung
cancer (NSCLC) | BMS | PD-1 | 40
49 |
| PD-L1 | 39 |
| Merck | PD-1 | 58,
59 |
| Roche/Genentech | PD-L1 | 45 |
| AstraZeneca/MedImmune | PD-L1 | 54,
57 |
| Renal cell cancer (RCC) | BMS | PD-1 | 38,
40, 42, 46,
49 |
| PD-L1 | 39 |
| Roche/Genentech | PD-L1 | 45 |
Urothelial bladder
cancer (UBC) | Merck | PD-1 | 56 |
| Roche/Genentech | PD-L1 | 47 |
| Hodgkin’s lymphoma | BMS | PD-1 | 50 |
| Head and neck cancer | Merck | PD-1 | 55 |
| Roche/Genentech | PD-L1 | 45,
53 |
| AstraZeneca/MedImmune | PD-L1 | 54 |
| Triple negative breast
cancer | Merck | PD-1 | 52 |
| Roche/Genentech | PD-L1 | 62 |
Consistent with the concept that the tumor evades host immune response
through engagement of PD-L1 with PD-1 on T cells, early studies suggested a
correlation between PD-L1 expressed by the tumor and poor prognosis. However,
several studies indicated a lack of correlation or even a positive association of
PD-L1 expression on tumor cells with lymphocyte infiltration and better
prognosis.28 A recent
study reported a negative feedback loop, whereby activated T cells infiltrating the
tumor environment produce proinflammatory cytokines, such as IFNγ, that
induce the up-regulation of PD-L1 on tumor cells. PD-L1 interaction with PD-1 on
tumor-infiltrating T cells suppresses T-cell functions.61 Therefore, PD-L1 expression in tumor cells
possibly indicates preexisting immune responses.
Based on the mechanism of PD-1/PD-L1 expression, PD-L1 expression by tumor
cells has been suggested as a biomarker for predicting the clinical response to PD-1
blockade therapy. Several clinical studies evaluated a correlation between
tumor-associated PD-L1 expression and the clinical response to PD-1 blocking agents,
and there seemed to be a trend of positive association. However, tumor expression of
PD-L1 is apparently not an absolute biomarker because not all patients with PD-L1+
tumors respond to PD-1 blockade, and some patients with PD-L1-(PD-L1 negative)
tumors are still responsive to PD-1 therapy.62, 63 Considering the
inducible nature of PD-L1 and the fact that many other PD-1/PD-L interactions are
possibly affected by PD-1 pathway blockade along with tumor cells and TIL
interactions, tumor PD-L1 expression as a single marker is not an optimal biomarker
of the response to PD-1-targeted immunotherapy. Therefore, it is imperative to
identify reliable biomarkers to select patients who can benefit from this
therapy.
V. COMBINATION THERAPY WITH PD-1 PATHWAY BLOCKADE
Because PD-1 plays a critical role in T-cell exhaustion, the efficacy of
other immunotherapies attempting to restore the function of exhausted T cells might
be enhanced by simultaneously blocking PD-1 signaling. In addition, combinations
with other therapeutic strategies may enhance treatments targeting PD-1. It has been
shown that PD-1 blockade rescues the less exhausted CD8 T cells expressing
intermediate levels of PD-1, whereas exhausted cells with high levels of PD-1
respond poorly and are unlikely to be reversed by the treatment.64 Several studies have shown that a
certain level of preexisting antigen-specific T cells is essential to better respond
to blockade of the PD-1 pathway. Therefore, combining PD-1 pathway blockade with
other therapies that possibly stimulate T-cell responses or interrupt other negative
signaling pathways could generate a synergistic effect.
Therapeutic vaccination in chronic infection or cancer has been shown to
have limited efficacy due to T-cell exhaustion.65 In chronic viral infection, immunization with recombinant
vaccinia virus vectors encoding LCMV glycoprotein (rVV-LCMV GP33) had a minimal
effect on enhancing CD8 T-cell response, but combined PD-L1 blockade significantly
improved LCMV-specific CD8 T-cell response and virus control.66 Furthermore, PD-L1 blockade
markedly enhanced antitumor T-cell response driven by granulocyte-macrophage
colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapy in mouse
models of melanoma and colon carcinoma.67 This result indicates that blocking PD-1 signaling can
enhance the efficacy of therapeutic vaccination. Currently, clinical trials
assessing the efficacy of multipeptide melanoma vaccines in combination with PD-1
blockade are ongoing ({"type":"clinical-trial","attrs":{"text":"NCT01176474","term_id":"NCT01176474"}}NCT01176474, {"type":"clinical-trial","attrs":{"text":"NCT01176461","term_id":"NCT01176461"}}NCT01176461) and the effect of combining
dendritic cell-based tumor vaccines with PD-1 blockade is being tested in several
types of cancer including RCC and multiple myeloma ({"type":"clinical-trial","attrs":{"text":"NCT01067287","term_id":"NCT01067287"}}NCT01067287, {"type":"clinical-trial","attrs":{"text":"NCT01441765","term_id":"NCT01441765"}}NCT01441765,
{"type":"clinical-trial","attrs":{"text":"NCT01096602","term_id":"NCT01096602"}}NCT01096602).
The severity of T-cell exhaustion has been shown to be correlated with
coexpression of multiple inhibitory receptors including PD-1, cytotoxic
T-lymphocyte-associated antigen 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3),
T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3), CD160, and
2B4.68 During chronic LCMV
infection, Tim-3 or LAG-3 blockade alone had a minimal effect on rescuing
virus-specific CD8 T cells, but combining with PD-1 pathway blockade synergistically
improved LCMV-specific CD8 T-cell response and virus control.68, 69 In addition, in murine cancer models, PD-1 pathway blockade
in combination with blocking Tim-3, LAG-3, or CTLA-4 was more effective in restoring
antitumor immunity and promoting tumor regression than targeting either pathway
alone.70–72 An additive or synergistic effect
on rescuing T cells by combined blockade of different inhibitory receptors indicates
their nonredundant roles and the complex regulatory mechanisms underlying T-cell
dysfunction. Recently, a clinical evaluation of PD-1 and CTLA-4 combination blockade
reported a higher rate of clinical response than single therapy in patients with
advanced melanoma.42 Dual blockade
of PD-1 and LAG-3 is being tested in solid tumors ({"type":"clinical-trial","attrs":{"text":"NCT01968109","term_id":"NCT01968109"}}NCT01968109).
The effect of manipulating stimulatory or inhibitory cytokines can be
enhanced when combined with PD-1 pathway blockade. IL-10 is an immunosuppressive
cytokine involved in T-cell exhaustion and blocking the IL-10 signal leads to
restoration of T-cell function and viral clearance in chronic LCMV
infection.73 Combined
blockade of the IL-10 receptor and PD-1 pathway further enhanced virus-specific
T-cell response and virus control during chronic LCMV infection.74 Previously, we found that
administration of IL-2, an immunostimulatory cytokine, during chronic infection
resulted in the rescue of exhausted T cells and better viral control.75 Combined IL-2 treatment and PD-1
pathway blockade had a synergistic effect on augmenting virus-specific CD8 T-cell
response and reducing viral load in chronic LCMV infection.76 IL-21 enhances cytolytic activity
of CD8 T cells and NK cells and recombinant IL-21 (rIL-21) administration has
demonstrated potent antitumor activity.77 In preclinical murine tumor models, rIL-21 administration
combined with PD-1 blockade further enhanced antitumor responses.78 Clinical evaluation of combination
treatment with rIL-21 and the anti-PD-1 antibody has recently been performed in
advanced or metastatic solid tumors.79
Adoptive transfer of T cells is an effective immunotherapeutic approach to
restore the antiviral or antitumor immune response. However, under the influence of
continuous antigen exposure, transferred cells become dysfunctional. Therefore,
blocking the PD-1/PD-L interaction can further augment the therapeutic efficacy of
adoptively transferred cells. Our recent work has shown that in chronic LCMV
infection, the therapeutic effects of naïve antigen-specific CD4 T-cell
transfer were further enhanced by blocking the PD-1 pathway, resulting in greater
functionality of LCMV-specific CD8 T cells and in a further reduction of viral
load.80 In tumor mouse
models, combined therapy of adoptive cell transfer and PD-1 pathway blockade has
shown a synergistic effect on tumor regression than single treatment. Blocking PD-1
increased the number of transferred cells at the tumor site, and this was associated
with greater T-cell proliferation and increased expression of IFNγ and the
IFNγ-inducible chemokine at the tumor site, facilitating immune cell
infiltration.81
IFNα has potent antitumor effects, but at the same time it can
induce expression of PD-1 and its ligands. Preclinical studies have shown that the
combination of IFNα therapy or IFNα-transduced cancer vaccines with
PD-1 pathway blockade further enhances antitumor immunity in tumor-bearing
mice.82, 83 This combination therapy suggests a promising
candidate for cancer treatment, and combined treatment with IFNα-2b and the
anti-PD-1 antibody is being tested or planned in patients with melanoma or RCC
({"type":"clinical-trial","attrs":{"text":"NCT02089685","term_id":"NCT02089685"}}NCT02089685, {"type":"clinical-trial","attrs":{"text":"NCT02112032","term_id":"NCT02112032"}}NCT02112032, {"type":"clinical-trial","attrs":{"text":"NCT02339324","term_id":"NCT02339324"}}NCT02339324). Furthermore, the combination of PD-1
blockade and the treatment with an antiangiogenic agent blocking the vascular
endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) interaction has revealed a
synergistic antitumor effect in a murine cancer model. 84 Based on the synergistic effects found from
preclinical studies, many combination therapies are being evaluated for cancer
patients.
VI. CONCLUSION
Cancer clinical trials targeting the PD-1 pathway have achieved a very high
rate of antitumor response. Currently, monotherapies targeting PD-1 or PD-L1 and
combination therapies with various immunotherapeutic strategies, including
checkpoint inhibitors, tumor vaccines, chemotherapy, and antiangiogenic agents, are
being evaluated in different types of cancer. It is important to assess different
combination therapies for those who do not respond to PD-1 blockade therapy. The
clinical evaluation of the PD-1 blocking agents is currently focused on cancer
treatment, but the therapies targeting the PD-1 pathway also have potential for
treating chronic infections. Still, the molecular mechanisms associated with the
PD-1 pathway regulating T-cell exhaustion and the way in which PD-1 signaling is
altered upon blocking the PD-1/PD-L interaction to restore exhausted T cells remain
to be determined. It is also essential to identify the predictive biomarkers to
personalize the therapy.
Acknowledgments
This work was supported by the National Institutes of Health grants AI30048
and AI56299 to R.A.
ABBREVIATIONS
| HCV | Hepatitis C virus |
| HIV | human immunodeficiency virus |
| LAG-3 | lymphocyte-activation gene-3 |
| LCMV | lymphocytic choriomeningitis virus |
| PD-1 | programmed cell death-1 |
| PD-L | programmed cell death-1 ligand |
| PD-L1 | programmed cell death-1 ligand-1 |
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