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Major progress has been made toward our understanding of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway (referred to as the PD pathway). mAbs are already being used to block the PD pathway to treat human cancers (anti-PD therapy), especially advanced solid tumors. This therapy is based on principles that were discovered through basic research more than a decade ago, but the great potential of this pathway to treat a broad spectrum of advanced human cancers is just now becoming apparent. In this Review, we will briefly review the history and development of anti-PD therapy, from the original benchwork to the most up-to-date clinical results. We will then focus the discussion on three basic principles that define this unique therapeutic approach and highlight how anti-PD therapy is distinct from other immunotherapeutic approaches, namely tumor site immune modulation, targeting tumor-induced immune defects, and repairing ongoing (rather than generating de novo) tumor immunity. We believe that these fundamental principles set the standard for future immunotherapies and will guide our efforts to develop more efficacious and less toxic immune therapeutics to treat human cancers.

Lieping Chen describes how his discoveries with PD-L1 yielded life-saving treatments for several cancers.

Cancer immunotherapy targeting the PD-1/PD-L1 pathway has demonstrated efficacy across a range of common solid tumors and some hematopoietic malignancies. Despite these groundbreaking successes, the clinical development of other ‘checkpoint inhibitors’ targeting molecules like TIM-3, TIGIT, ICOS and others, has largely fallen short, often showing minimal clinical benefit even in combination with anti-PD therapy. This article explores three key hypotheses that help explain the disparity in therapeutic success: (1) the absence of tumor- specific immunosuppressive logic in many checkpoint targets, (2) the dominance—but not redundancy—of immune evasion mechanisms within the tumor microenvironment (TME), and (3) the emergence of therapy-induced resistance. This is not intended as a comprehensive review of the literature. Instead, it highlights select evidence to explain past failures and to illuminate a more strategic, biologically informed path forward.

T cell rejuvenation by PD-1/PD-L1 blockade, despite emerging as a highly promising therapy for advanced cancers, is only beneficial for a minority of treated patients. There is evidence that a lack of efficient T cell activation may be responsible for the failure. Here, we demonstrate that IL-21 can be targeted to tumor-reactive T cells by fusion of IL-21 to anti-PD-1 antibody. To our surprise, the fusion protein PD-1Ab21 promotes the generation of memory stem T cells (T SCM ) with enhanced cell proliferation. PD-1Ab21 treatment show potent antitumor effects in established tumor-bearing mice accompanied with an increased frequency of T SCM and robust expansion of tumor-specific CD8 + T cells with a memory phenotype, and is superior to a combination of PD-1 blockade and IL-21 infusion. Therefore, we have developed a potential strategy to improve the therapeutic effects of immune checkpoint blockade by simultaneously targeting cytokines to tumor-reactive T cells. The lack of an efficient anti-tumor T cell response contributes to the failure of anti-PD1 therapy. Here, the authors show a potential strategy to improve the therapeutic effects of anti-PD-1 antibody by simultaneously targeting IL-21 to tumor-reactive T cells in vivo.

Semaphorin-4A (Sema4A) has been implicated in the co-stimulation of T cells and drives Th1 immune responses by binding to the receptor T-cell immunoglobulin and mucin domain protein 2 (Tim-2) in mice. Here we show that human, but not murine, Sema4A is preferentially expressed on antigen-presenting cells, and co-stimulates CD4 + T-cell proliferation and drives Th2 responses. By employing two independent cloning strategies, we demonstrate that Immunoglobulin-like transcript 4 (ILT-4) is a receptor for human SEMA4A (hSEMA4A) on activated CD4 + T cells. We also find hSEMA4A to be highly expressed in human asthmatic lung tissue, implying its potential function in disease pathogenesis. Our study defines a different biological function of hSEMA4A from its murine homolog through its binding to the receptor of ILT-4 to co-stimulate CD4 + T cells and regulate Th2 cells differentiation. Semaphorin-4A is a cell surface protein with known functions in neural development and immune regulation, but the mechanism for immune modulation is unclear. Here the authors show that ILT-4, previously found on myeloid cells, is the receptor of Semaphorin-4A on activate human CD4 T cells for mediating T cell co-stimulation.

Hidradenitis suppurativa (HS) is a chronic, heterogeneous inflammatory skin disorder with limited therapeutic options. The immune checkpoint receptor TIGIT is emerging as a regulator of chronic inflammation, yet its role in HS remains unknown. Here, we investigated TIGIT and its ligands in HS using tissue profiling, transcriptomics, and an ex vivo functional explant model. A tissue microarray containing 52 HS, 9 ruptured follicular cysts, and 4 normal skin samples demonstrated significantly increased TIGIT expression in HS lesions. In contrast, the TIGIT ligand PVRL3 was significantly decreased in HS, a finding also observed in a publicly available RNA-seq dataset. Because TIGIT suppresses inflammation only when adequately engaged by its ligands, reduced PVRL3 may impair inhibitory checkpoint signaling in HS. To test whether TIGIT engagement could suppress HS inflammation, we developed an ex vivo explant model using freshly obtained HS lesional tissue. The system was validated using triamcinolone, a corticosteroid, which consistently reduced IL-6 production. Treatment with a TIGIT agonist antibody significantly reduced IL-6 by 72 hours. These findings provide the first functional evidence that TIGIT activation attenuates inflammatory pathways in HS, supporting TIGIT agonism as a potential therapeutic strategy.

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Recent studies in animal models of viral infection indicate that the interaction between the inhibitory receptor, programmed death (PD)-1, on lymphocytes and its ligand (PD-L1) play a critical role in T-cell exhaustion by inducing T-cell inactivation. High PD-1 expression levels by peripheral T-lymphocytes and the possibility of improving T-cell function by blocking PD-1-mediated signaling confirm the importance of this inhibitory pathway in inducing T-cell exhaustion. We studied T-cell exhaustion and the effects of PD-1 and PD-L1 blockade on intrahepatic infiltrating T-cells in our recently developed mouse model of HBV persistence. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1-expressing CD8+ and CD4+ T cells in mice with HBV persistence, but PD-1 upregulation was resolved in mice which had cleared HBV. The Intrahepatic CD8+ T-cells expressed higher levels of PD-1 and lower levels of CD127 in mice with HBV persistence. Blockade of PD-1/PD-L1 interactions increased HBcAg-specific interferon (IFN)-γ production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with PD-L1 by an anti-PD-1 monoclonal antibody (mAb) reversed the exhausted phenotype in intrahepatic T lymphocytes and viral persistence to clearance of HBV in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence of HBV infection in a mouse animal model, suggesting that the anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection.

Key Points The immune response against cancer is tightly regulated through a set of stimulatory and inhibitory molecules expressed by cancer cells, stromal cells (including APCs) and haematopoietic cells in the tumour microenvironment. Expression of inhibitory members of the co-stimulatory B7 family, such as B7-H1 and B7-H4, is often up-regulated in the tumour microenvironment by local factors including cytokines. Inhibitory B7 molecules mediate various mechanisms to evade tumour-antigen-specific T-cell immunity, including T-cell apoptosis, anergy and exhaustion, forming a molecular shield to protect tumour cells from lysis, and functional modulations of antigen-presenting cells and regulatory T cells. Expression of inhibitory B7 molecules in the tumour microenvironment correlates with poor prognosis in several types of human cancer. Therefore, these molecules might be potential biomarkers to predict therapeutic outcome. Blockade of signalling through the inhibitory B7 molecules is a promising strategy that might work alone or in combination with other modalities to improve current tumour therapies. This Review describes how the expression of inhibitory members of the B7 family, particularly B7-H1 and B7-H4, by cancer cells, stromal cells and haematopoietic cells in the tumour microenvironment is regulated and acts to inhibit T-cell immunity, as well as the therapeutic implications. The B7 family consists of activating and inhibitory co-stimulatory molecules that positively and negatively regulate immune responses. Recent studies have shown that human and rodent cancer cells, and stromal cells and immune cells in the cancer microenvironment upregulate expression of inhibitory B7 molecules and that these contribute to tumour immune evasion. In this Review, we focus on the roles of these B7 molecules in the dynamic interactions between tumours and the host immune system, including their expression, regulation and function in the tumour microenvironment. We also discuss novel therapeutic strategies that target these inhibitory B7 molecules and their signalling pathways to treat human cancer.

Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti-programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.