Co-Stimulatory Receptors in Cancers and Their Implications for Cancer Immunotherapy

Immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 therapeutic agents, are now approved by the Food and Drug Administration for treatment of various types of cancer. However, the therapeutic efficacy of ICIs varies among patients and cancer types. Moreover, most patients do not develop durable antitumor responses after ICI therapy due to an ephemeral reversal of T-cell dysfunction. As co-stimulatory receptors play key roles in regulating the effector functions of T cells, activating co-stimulatory pathways may improve checkpoint inhibition efficacy, and lead to durable antitumor responses. Here, we review recent advances in our understating of co-stimulatory receptors in cancers, providing the necessary groundwork for the rational design of cancer immunotherapy.

Heterogeneity of Human γδ T Cells and Their Role in Cancer Immunity

The γδ T cells are unconventional lymphocytes that function in both innate and adaptive immune responses against various intracellular and infectious stresses. The γδ T cells can be exploited as cancer-killing effector cells since γδ TCRs recognize MHC-like molecules and growth factor receptors that are upregulated in cancer cells, and γδ T cells can differentiate into cytotoxic effector cells. However, γδ T cells may also promote tumor progression by secreting IL-17 or other cytokines. Therefore, it is essential to understand how the differentiation and homeostasis of γδ T cells are regulated and whether distinct γδ T cell subsets have different functions. Human γδ T cells are classified into Vδ2 and non-Vδ2 γδ T cells. The majority of Vδ2 γδ T cells are Vγ9δ2 T cells that recognize pyrophosphorylated isoprenoids generated by the dysregulated mevalonate pathway. In contrast, Vδ1 T cells expand from initially diverse TCR repertoire in patients with infectious diseases and cancers. The ligands of Vδ1 T cells are diverse and include the growth factor receptors such as endothelial protein C receptor. Both Vδ1 and Vδ2 γδ T cells are implicated to have immunotherapeutic potentials for cancers, but the detailed elucidation of the distinct characteristics of 2 populations will be required to enhance the immunotherapeutic potential of γδ T cells. Here, we summarize recent progress regarding cancer immunology of human γδ T cells, including their development, heterogeneity, and plasticity, the putative mechanisms underlying ligand recognition and activation, and their dual effects on tumor progression in the tumor microenvironment.

Expressions and Clinical Significance of Tim-3 and PD-1 on Peripheral Blood γδ T Cells in Patients With Colon Cancer / 胃肠病学

Background: The occurrence of tumor is closely related to the function of immune system. As an effector cell of innate immunity, the function of γδ T cells is reported to be regulated by co-stimulatory molecules. T-cell immunoglobulin mucin-3 (Tim-3) and programmed death-1 (PD-1), two critical inhibitory co-stimulatory molecules, may affect the immune function of T lymphocytes via binding with their ligands, thus mediating the immune escape of tumor cells. Aims: To investigate the expressions and clinical significance of Tim-3 and PD-1 on γδ T cells in peripheral blood of colon cancer patients. Methods: Peripheral blood samples of 44 colon cancer patients were collected preoperatively at the First Affiliated Hospital of Soochow University from Dec. 2017 to Jun. 2018. Forty healthy volunteers were served as controls. The peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. Expressions of Tim-3 and PD-1 on γδ T cells were detected by flow cytometry, and their correlations with tumor clinicopathological characteristics were analyzed. Results: The proportions of Tim-3+, PD-1+ and Tim-3+PD-1+ γδ T cells in peripheral blood of colon cancer patients were significantly higher than those of healthy volunteers (P0.05). Conclusions: Tim-3 and PD-1 are highly expressed on γδ T cells in peripheral blood of colon cancer patients and associated with the clinicopathological stage of tumor. Expressions of Tim-3 and PD-1 on peripheral blood γδ T cells might be the promising objective indicators for evaluating the development and progression of colon cancer.

Mucosal-associated invariant T cells and tumors / 中国药理学通报

Mucosal-assooiated invariant T(MAIT) cells are an evolutionarily highly conserved T lymphocyte subsets with the innate functions similar to innate natural killer T(iNKT) cells. MAIT cells are defined by their invariant T cell receptors (TCR)-alpha chain and restrictive major histocompatibility complex (MHC) related protein-! (MR1) , and identify antigens through the MR1, secreting a variety of cytokines after being activated, directly or indirectly involved in the body's immune re-sponses. MAIT cells are also abundant in human peripheral blood and many tissues. They are closely related to the occurrence and development of various infectious diseases, autoimmune diseases and malignant tumors. This article mainly reviews the research on MAIT cells in tumor diseases.

γδ T Cells Contribute to the Outcome of Murine Fulminant Viral Hepatitis via Effector Cytokines TNF-α and IFN-γ / 华中科技大学学报（医学）（英德文版）

The mechanisms involved in virus-induced severe hepatitis have not been fully elucidated.In this study,we investigated the role of gamma delta T cell receptors (γδ) T cells in the pathogenesis of fulminant viral hepatitis (FVH) induced by murine hepatitis virus strain 3 (MHV-3).The model of FVH was established by intraperitoneal injection of MHV-3 into Balb/cJ mice.The survival days of mice,and the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were examined.The proportions ofγδ T cells in blood,spleen and liver,and cytokines secreted by hepatic γδ T cells were analyzed by flow cytometry.The function of hepatic γδ T cells was examined by cytotoxicity assay.Balb/cJ mice died in 3 to 6 days post MHV-3 infection,with severe hepatic necrosis and significant augmentation of serum ALT and AST levels.The proportions of γδ T ceils in blood,spleen and liver were significantly increased post MHV-3 infection,while those of the early activating molecule CD69-expressing γδ T cells and productions of cytokines tumor necrosis factor-alpha (TNF-α) and interferon-γ (IFN-γ) increased remarkably in the liver.These highly activated liver γδ T cells were cytotoxic to MHV-3-infected hepatocytes in vitro and this effect of liver γδ T cells against hepatocytes might involve the TNF-α and IFN-γ pathway.These results demonstrated that γδ T cells might contribute to the pathogenesis ofMHV-3-induced FVH through the effector cytokines TNF-α and IFN-γ.

γδ T Cells Contribute to the Outcome of Murine Fulminant Viral Hepatitis via Effector Cytokines TNF-α and IFN-γ / 华中科技大学学报（医学）（英德文版）

The mechanisms involved in virus-induced severe hepatitis have not been fully elucidated.In this study,we investigated the role of gamma delta T cell receptors (γδ) T cells in the pathogenesis of fulminant viral hepatitis (FVH) induced by murine hepatitis virus strain 3 (MHV-3).The model of FVH was established by intraperitoneal injection of MHV-3 into Balb/cJ mice.The survival days of mice,and the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were examined.The proportions ofγδ T cells in blood,spleen and liver,and cytokines secreted by hepatic γδ T cells were analyzed by flow cytometry.The function of hepatic γδ T cells was examined by cytotoxicity assay.Balb/cJ mice died in 3 to 6 days post MHV-3 infection,with severe hepatic necrosis and significant augmentation of serum ALT and AST levels.The proportions of γδ T ceils in blood,spleen and liver were significantly increased post MHV-3 infection,while those of the early activating molecule CD69-expressing γδ T cells and productions of cytokines tumor necrosis factor-alpha (TNF-α) and interferon-γ (IFN-γ) increased remarkably in the liver.These highly activated liver γδ T cells were cytotoxic to MHV-3-infected hepatocytes in vitro and this effect of liver γδ T cells against hepatocytes might involve the TNF-α and IFN-γ pathway.These results demonstrated that γδ T cells might contribute to the pathogenesis ofMHV-3-induced FVH through the effector cytokines TNF-α and IFN-γ.