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Programmed cell death–1 (PD-1)–targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate Tcells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit Tcell activation when APCs express substantial amounts of CD80. In knock-in mice in which cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1.These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal,while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.

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.

Immune checkpoint blockade of the inhibitory immune receptors PD-L1, PD-1 and CTLA-4 has emerged as a successful treatment strategy for several advanced cancers. Here we demonstrate that miR-424(322) regulates the PD-L1/PD-1 and CD80/CTLA-4 pathways in chemoresistant ovarian cancer. miR-424(322) is inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. High levels of miR-424(322) in the tumours are positively correlated with the progression-free survival of ovarian cancer patients. Mechanistic investigations demonstrated that miR-424(322) inhibited PD-L1 and CD80 expression through direct binding to the 3′-untranslated region. Restoration of miR-424(322) expression reverses chemoresistance, which is accompanied by blockage of the PD-L1 immune checkpoint. The synergistic effect of chemotherapy and immunotherapy is associated with the proliferation of functional cytotoxic CD8+ T cells and the inhibition of myeloid-derived suppressive cells and regulatory T cells. Collectively, our data suggest a biological and functional interaction between PD-L1 and chemoresistance through the microRNA regulatory cascade. Resistance to chemotherapy occurs in many ovarian cancer cases. Here, the authors show that mir-424(322) expression restores the sensitivity of ovarian cancer cells to chemotherapy by blocking the PD-L1 immune checkpoint, and find that combining immunotherapy and chemotherapy has a synergistic effect.

Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor CD4+ T cells increased serum IFN-γ but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor CD8+ T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment CD8+ T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1-mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptor expressed by CD8+ T cells, and the tissue environment in which the signaling occurs.

MHC regulator in cancers Using whole transcriptome sequencing, Steidl et al . identify recurrent gene translocations in B-cell lymphomas that involve the class II transactivator CIITA , the 'master regulator' of the major histocompatibility complex. These translocations downregulate cell surface HLA class II and, with some fusion partners, lead to overexpression of CD274/CD273 ligands, potentially reducing the anti-tumour immune response against these lymphomas. Recurrent rearrangements of CIITA may represent a genetic mechanism that is involved more widely in interactions between tumours and their microenvironment in lymphoid cancers. Using whole-transcriptome sequencing, this paper identifies recurrent gene translocations in B-cell lymphomas that involve the MHC class II transactivator CIITA. These translocations lead to downregulation of cell surface HLA class II expression and, in the case of some fusion partners, overexpression of CD274/CD273 ligands, which have the potential to reduce the antitumour response against these lymphomas. Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features 1 , 2 . In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq). Here we show a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA ( MHC2TA ) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of various in-frame gene fusions, and we report that CIITA gene alterations impact survival in primary mediastinal B-cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These receptor–ligand interactions have been shown to impact anti-tumour immune responses in several cancers 3 , whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity 4 . Thus, our findings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumour–microenvironment interactions across a spectrum of lymphoid cancers.

Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration and there are contradictory data about their roles in regulatory T cell (Treg) function. Here we show activated Tregs and CD4 effector T cells (Teffs) use PD-1/PD-L1 and CD80/PD-L1, respectively, to regulate transendothelial migration across lymphatic endothelial cells (LECs). Antibody blockade of Treg PD-1, Teff CD80 (the alternative ligand for PD-L1), or LEC PD-L1 impairs Treg or Teff migration in vitro and in vivo. PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate zipper junctional VE-cadherin, and through NFκB-p65 to up-regulate VCAM-1 expression on LECs. CD80/PD-L1 signaling up-regulates VCAM-1 through ERK and NFκB-p65. PD-1 and CD80 blockade reduces tumor egress of PD-1 high fragile Tregs and Teffs into draining lymph nodes, respectively, and promotes tumor regression. These data provide roles for PD-L1 in cell migration and immune regulation. The Programmed death-1 (PD-1) and its ligand PD-L1 are critical checkpoints in the regulation of immune responses. Here the authors implicate PD-L1 signalling at lymphatic endothelium in the regulation of transendothelial migration of T cells.

Targeted approaches to treat autoimmune diseases would improve upon current therapies that broadly suppress the immune system and lead to detrimental side effects. Antigen-specific tolerance was induced using poly(lactide-co-glycolide) nanoparticles conjugated with disease-relevant antigen to treat a model of multiple sclerosis. Increasing the nanoparticle dose and amount of conjugated antigen both resulted in more durable immune tolerance. To identify active tolerance mechanisms, we investigated downstream cellular and molecular events following nanoparticle internalization by antigen-presenting cells. The initial cell response to nanoparticles indicated suppression of inflammatory signaling pathways. Direct and functional measurement of surface MHC-restricted antigen showed positive correlation with both increasing particle dose from 1 to 100 μg/mL and increasing peptide conjugation by 2-fold. Co-stimulatory analysis of cells expressing MHC-restricted antigen revealed most significant decreases in positive co-stimulatory molecules (CD86, CD80, and CD40) following high doses of nanoparticles with higher peptide conjugation, whereas expression of a negative co-stimulatory molecule (PD-L1) remained high. T cells isolated from mice immunized against myelin proteolipid protein (PLP139–151) were co-cultured with antigen-presenting cells administered PLP139–151-conjugated nanoparticles, which resulted in reduced T cell proliferation, increased T cell apoptosis, and a stronger anti-inflammatory response. These findings indicate several potential mechanisms used by peptide-conjugated nanoparticles to induce antigen-specific tolerance. Peptide-conjugated nanoparticles induce antigen-specific tolerance in models of autoimmunity. Kuo et al. investigated cellular and molecular mechanisms of antigen-presenting cells following nanoparticle internalization. Increasing peptide conjugation and delivering higher nanoparticle doses both contributed to enhanced antigen presentation, as well as reductions in co-stimulatory expression and effector T cell responses.

Radiotherapy (RT) is considered immunogenic, but clinical data demonstrating RT-induced T cell priming are scarce. Here, we show in a mouse tumor model representative of human lymphocyte-depleted cancer that RT enhanced spontaneous priming of thymus-derived (FOXP3+Helios+) Tregs by the tumor. These Tregs acquired an effector phenotype, populated the tumor, and impeded tumor control by a simultaneous, RT-induced CD8+ cytotoxic T cell (CTL) response. Combination of RT with CTLA-4 or PD-1 blockade, which enables CD28 costimulation, further increased this Treg response and failed to improve tumor control. We discovered that upon RT, the CD28 ligands CD86 and CD80 differentially affected the Treg response. CD86, but not CD80, blockade prevented the effector Treg response, enriched the tumor-draining lymph node migratory conventional DCs that were positive for PD-L1 and CD80 (PD-L1+CD80+), and promoted CTL priming. Blockade of CD86 alone or in combination with PD-1 enhanced intratumoral CTL accumulation, and the combination significantly increased RT-induced tumor regression and OS. We advise that combining RT with PD-1 and/or CTLA-4 blockade may be counterproductive in lymphocyte-depleted cancers, since these interventions drive Treg responses in this context. However, combining RT with CD86 blockade may promote the control of such tumors by enabling a CTL response.

Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the ‘helpless’ CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections. Boosting antiviral immunity It's common in chronic viral disease for the immune system to grow accustomed to the infection. Normally CD8 T cells retain a ‘memory’ of the viruses they encounter, so they can respond rapidly to a new infection. In a chronic infection the memory cells lose this capacity, but the nature of this ‘exhausted’ state is not well understood. Barber et al . have now found a possible cause in a study of a mouse infection model. The inhibitory immune receptor gene PD-1 is much more active in exhausted than in normal CD8 T cells, and administration of antibodies that block PD-1 action restores function in virus-specific T cells and also reduces virus levels. The discovery of a T-cell exhaustion mechanism suggests a route to immunological strategies for treating chronic viral infections.