Review
Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway

https://doi.org/10.1016/j.molmed.2014.10.009Get rights and content

Highlights

  • The PD-1/PD-L1 pathway inhibits T cell functions.

  • The PD-1/PD-L1 pathway functions as immune evasion in some cancers.

  • Clinical trials targeting PD-1 and PD-L1 show impressive response rates.

The programmed death 1 (PD-1) receptor and its ligands programmed death ligand 1 (PD-L1) and PD-L2, members of the CD28 and B7 families, play critical roles in T cell coinhibition and exhaustion. Overexpression of PD-L1 and PD-1 on tumor cells and tumor-infiltrating lymphocytes, respectively, correlates with poor disease outcome in some human cancers. Monoclonal antibodies (mAbs) blockading the PD-1/PD-L1 pathway have been developed for cancer immunotherapy via enhancing T cell functions. Clinical trials with mAbs to PD-1 and PD-L1 have shown impressive response rates in patients, particularly for melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), and bladder cancer. Further studies are needed to dissect the mechanisms of variable response rate, to identify biomarkers for clinical response, to develop small-molecule inhibitors, and to combine these treatments with other therapies.

Section snippets

Expression of PD-1 and its ligands

The PD-1 (CD279) (see Glossary) receptor can be detected at the cell surface of T cells during thymic development and in the periphery of several types of hematopoietic cell following T cell receptor (TCR) signaling and cytokine stimulation. PD-1 is expressed on CD4CD8 thymocytes and inducibly expressed on peripheral CD4+ and CD8+ T cells, B cells, monocytes, natural killer (NK) T cells, and some dendritic cells (DCs) 1, 2. Persistent expression of PD-1 on T cells induces T cell exhaustion [3]

Structures of PD-1 and its ligands

Structurally, PD-1 is a type I transmembrane receptor and belongs to the Ig superfamily (IgSF). Although it is functionally related to the costimulatory/coinhibitory receptors CD28, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and inducible T cell costimulator (ICOS), PD-1 has important structural and functional differences. Other receptors in the CD28 family are disulfide-linked dimers; however, structural and cell-surface studies demonstrated that PD-1 is a monomeric glycoprotein [19]

Prognostic relevance of PD-1 and its ligands in human malignancies

Persistent expression of PD-1 by T cells is highly indicative of an exhausted phenotype, noted by a decrease in effector function 4, 5. This phenotype has been observed in various types of tumor-infiltrating lymphocyte (TIL) and linked to poor prognosis and tumor recurrence, highlighting PD-1 as an important molecule in regulating antitumor activity (Table 1). Similar to PD-1, PD-L1 and PD-L2 also possess prognostic capacities in some human malignancies (Table 2). Some clinical studies

Mechanisms of anti-PD-1 and anti-PD-L1 immunotherapy

Appreciating the consequences of the upregulation of the PD-1/PD-L1/2 axis aids our progress in manipulating an immunosuppressive cancer microenvironment. The cytoplasmic tail of PD-1 contains two signaling motifs. One is an immunoreceptor tyrosine-based inhibitory motif (ITIM) and the other is an immunoreceptor tyrosine-based switch motif (ITSM). Binding of PD-L1 or PD-L2 to PD-1 on activated T cells, along with TCR signaling, leads to phosphorylation of the cytoplasmic domain tyrosines and

Clinical trials of mAbs to PD-1

Pidilizumab (CT-011) was the first mAb to PD-1 to reach clinical trials [29] (Table 4). It was initially identified as a mAb binding to the B lymphoblastoid cell line that stimulated murine lymphocytes and showed antitumor activity in mice [30]. It stimulated human peripheral blood lymphocytes and enhanced cytotoxicity toward human tumor cell lines. The first Phase I trial with pidilizumab recruited patients with hematologic malignancies, including acute myeloid leukemia (AML), chronic

Clinical trials of mAbs to PD-L1

BMS-936559 is a fully human monoclonal IgG4 antibody that blocks PD-L1 [44] (Table 4). This blockade was shown to augment T cell proliferation in response to allogeneic dendritic cells in a mixed lymphocyte reaction, as well as antigen-specific T cell responses to cytomegalovirus (CMV) antigen and antitumor peptide responses in subjects treated with melanoma antigen peptide vaccines. BMS-936559 can reverse in vitro Treg-mediated suppression. Use of BMS-936559 in clinical trials was supported by

Clinical trials of PD-L2 Ig fusion protein

As an alternative strategy to mAbs, AMP-224 (B7-DC-Ig) was developed as a chimeric fusion protein between the extracellular domain of PD-L2 and an Fc portion of IgG2a (http://www.prnewswire.com/news-releases/glaxosmithkline-and-amplimmune-form-global-strategic-collaboration-99938599.html). In vivo studies suggested that this fusion protein can ameliorate disease by inducing immune responses to pathogens. Furthermore, the murine form of AMP-224 can enhance the therapeutic efficacy of vaccination

Concluding remarks

After success with ipilimumab in the treatment of malignant melanoma, the field of cancer immunotherapy continues to grow. Blockade of T cell inhibition allows restored antitumor immunity and has shown impressive results in clinical trials. Beyond the CTLA-4 pathway, T cell inhibition mediated by the PD-1/PD-L1 pathway is now the most studied and clinically developed cancer immunotherapy. Several mAbs to PD-1 or PD-L1 have been studied in Phase I trials and continue to be evaluated in Phase II

Acknowledgements

K.C.O. is supported by National Institutes of Health (NIH) F31CA183493. X.Z. is supported by NIH R01CA175495, Department of Defense Established Investigator Idea Development Award PC131008, and the Dr Louis Sklarow Memorial Trust.

Glossary

Cancer immunotherapy
treatments that use the host immune system to inhibit cancer.
Monoclonal antibody (mAb)
antibodies generated by immune cells derived from a single parent cell.
Programmed death 1 (PD-1)
a 288-amino acid cell-surface molecule, encoded in humans by the PDCD1 gene, that functions to negatively regulate immune responses.
Programmed death ligand 1 (PD-L1)
a 40-kDa type 1 transmembrane protein, encoded in humans by the CD274 gene, that suppresses the immune system in cancer, pregnancy,

References (88)

  • D.L. Barber

    Restoring function in exhausted CD8 T cells during chronic viral infection

    Nature

    (2006)
  • E.J. Wherry

    T cell exhaustion

    Nat. Immunol.

    (2011)
  • K.A. Hofmeyer

    The PD-1/PD-L1 (B7-H1) pathway in chronic infection-induced cytotoxic T lymphocyte exhaustion

    J. Biomed. Biotechnol.

    (2011)
  • L.M. Francisco

    The PD-1 pathway in tolerance and autoimmunity

    Immunol. Rev.

    (2010)
  • L.M. Francisco

    PD-L1 regulates the development, maintenance, and function of induced regulatory T cells

    J. Exp. Med.

    (2009)
  • S. Haxhinasto

    The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

    J. Exp. Med.

    (2008)
  • M.L. Thibult

    PD-1 is a novel regulator of human B-cell activation

    Int. Immunol.

    (2013)
  • K.J. Nicholas

    B cell responses to HIV antigen are a potent correlate of viremia in HIV-1 infection and improve with PD-1 blockade

    PLoS ONE

    (2013)
  • H. Dong

    B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion

    Nat. Med.

    (1999)
  • G.J. Freeman

    Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation

    J. Exp. Med.

    (2000)
  • Y. Latchman

    PD-L2 is a second ligand for PD-1 and inhibits T cell activation

    Nat. Immunol.

    (2001)
  • S.Y. Tseng

    B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells

    J. Exp. Med.

    (2001)
  • M. Atefi

    Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma

    Clin. Cancer Res.

    (2014)
  • A.T. Parsa

    Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma

    Nat. Med.

    (2007)
  • Y. Xiao

    RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance

    J. Exp. Med.

    (2014)
  • D.Y. Lin

    The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors

    Proc. Natl. Acad. Sci. U.S.A.

    (2008)
  • E. Lazar-Molnar

    Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2

    Proc. Natl. Acad. Sci. U.S.A.

    (2008)
  • R.V. Parry

    CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms

    Mol. Cell. Biol.

    (2005)
  • X. Zang et al.

    The B7 family and cancer therapy: costimulation and coinhibition

    Clin. Cancer Res.

    (2007)
  • L.B. John

    Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells

    Clin. Cancer Res.

    (2013)
  • M.A. Curran

    PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors

    Proc. Natl. Acad. Sci. U.S.A.

    (2010)
  • Z.C. Ding

    Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-Cell responses through the PD-1–PD-L1 Axis

    Cancer Res.

    (2014)
  • L. Deng

    Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice

    J. Clin. Invest.

    (2014)
  • R. Berger

    Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies

    Clin. Cancer Res.

    (2008)
  • B. Hardy

    Activation of human lymphocytes by a monoclonal antibody to B lymphoblastoid cells; molecular mass and distribution of binding protein

    Cancer Immunol. Immunother.

    (1995)
  • P. Armand

    Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international Phase II trial

    J. Clin. Oncol.

    (2013)
  • A. Patnaik

    Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors

    ASCO Meeting Abstracts

    (2012)
  • O. Hamid

    Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma

    N. Engl. J. Med.

    (2013)
  • A.I. Daud

    Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma (MEL): correlation of tumor PD-L1 expression with outcome [abstract]

  • R.M. Wong

    Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs

    Int. Immunol.

    (2007)
  • W. Wang

    PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+CD25Hi regulatory T cells

    Int. Immunol.

    (2009)
  • J.R. Brahmer

    Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates

    J. Clin. Oncol.

    (2010)
  • S.L. Topalian

    Safety, activity, and immune correlates of anti-PD-1 antibody in cancer

    N. Engl. J. Med.

    (2012)
  • J.R. Brahmer

    Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): survival and clinical activity by subgroup analysis

    ASCO Meeting Abstracts

    (2014)
  • Cited by (615)

    View all citing articles on Scopus
    *

    These authors contributed equally.

    View full text