Pro-tumor γδ T Cells in Human Cancer: Polarization, Mechanisms of Action, and Implications for Therapy (original) (raw)

γδ T Cells: Unexpected Regulators of Cancer Development and Progression

Trends in Cancer, 2017

Accumulating evidence suggests a role for γδ T cells as unexpected drivers of tumor development and progression. These protumoral γδ T cells are abundant in the tumor microenvironment in both mouse and human. They promote tumor progression by 1) inducing an immunosuppressive tumor microenvironment and angiogenesis via cytokine production; by 2) functioning as Treg/Th2-like cells; by 3) interfering with dendritic cell effector function; and by 4) inhibiting antitumor adaptive T cell immunity via the PD-1/PD-L1 pathway. Understanding how these cells are regulated and what their specific role in cancer is will provide insight for developing approaches that specifically target these cells and can thus improve the efficacy of cancer immunotherapies.

Cancer immunotherapy with γδ T cells: many paths ahead of us

Cellular & Molecular Immunology, 2020

γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effec...

Diversity of Tumor-Infiltrating, γδ T-Cell Abundance in Solid Cancers

Cells, 2020

γδ T-cells contribute to the immune response against many tumor types through their direct cytolytic functions and their capacity to recruit and regulate the biological functions of other immune cells. As potent effectors of the anti-tumor immune response, they are considered an attractive therapeutic target for immunotherapies, but their presence and abundance in the tumor microenvironment are not routinely assessed in patients with cancer. Here, we validated an antibody for immunohistochemistry analysis that specifically detects all γδ T-cell subpopulations in healthy tissues and in the microenvironment of different cancer types. Tissue microarray analysis of breast, colon, ovarian, and pancreatic tumors showed that γδ T-cell density varies among cancer types. Moreover, the abundance of γδ tumor-infiltrating lymphocytes was variably associated with the outcome depending on the cancer type, suggesting that γδ T-cell recruitment is influenced by the context. These findings also sugg...

Plasticity of γδT cells: impact on the anti-tumor response

The tumor immune microenvironment contributes to tumor initiation, progression, and response to therapy. Among the immune cell subsets that play a role in the tumor microenvironment, innate-like T cells that express T cell receptors composed of γ and δ chains (γδ T cells) are of particular interest. γδ T cells can contribute to the immune response against many tumor types (lymphoma, myeloma, melanoma, breast, colon, lung, ovary, and prostate cancer) directly through their cytotoxic activity and indirectly by stimulating or regulating the biological functions of other cell types required for the initiation and establishment of the anti-tumor immune response, such as dendritic cells and cytotoxic CD8+ T cells. However, the notion that tumor-infiltrating γδ T cells are a good prognostic marker in cancer was recently challenged by studies showing that the presence of these cells in the tumor microenvironment was associated with poor prognosis in both breast and colon cancer. These findings suggest that γδ T cells may also display pro-tumor activities. Indeed, breast tumor-infiltrating γδ T cells could exert an immunosuppressive activity by negatively regulating dendritic cell maturation. Furthermore, recent studies demonstrated that signals from the microenvironment, particularly cytokines, can confer some plasticity to γδ T cells and promote their differentiation into γδ T cells with regulatory functions. This review focuses on the current knowledge on the functional plasticity of γδ T cells and its effect on their anti-tumor activities. It also discusses the putative mechanisms underlying γδ T cell expansion, differentiation, and recruitment in the tumor microenvironment.

γδ T cells in cancer: a small population of lymphocytes with big implications

Clinical & Translational Immunology

cd T cells are a small population of mostly tissue-resident lymphocytes, with both innate and adaptive properties. These unique features make them particularly attractive candidates for the development of new cellular therapy targeted against tumor development. Nevertheless, cd T cells may play dual roles in cancer, promoting cancer development on the one hand, while participating in antitumor immunity on the other hand. In mice, cd T-cell subsets preferentially produce IL-17 or IFN-c. While antitumor functions of murine cd T cells can be attributed to IFNc + cd T cells, recent studies have implicated IL-17 + cd T cells in tumor growth and metastasis. However, in humans, IL-17producing cd T cells are rare and most studies have attributed a protective role to cd T cells against cancer. In this review, we will present the current knowledge and most recent findings on cd Tcell functions in mouse models of tumor development and human cancers. We will also discuss their potential as cellular immunotherapy against cancer.