Trends in Molecular Medicine
ReviewHuman cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway
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 CD4−CD8− 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,
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These authors contributed equally.