The Dual Roles of Human γδ T Cells: Anti-Tumor or Tumor-Promoting

Abstract

γδ T cells are the unique T cell subgroup with their T cell receptors composed of γ chain and δ chain. Unlike αβ T cells, γδ T cells are non-MHC-restricted in recognizing tumor antigens, and therefore defined as innate immune cells. Activated γδ T cells can promote the anti-tumor function of adaptive immune cells. They are considered as a bridge between adaptive immunity and innate immunity. However, several other studies have shown that γδ T cells can also promote tumor progression by inhibiting anti-tumor response. Therefore, γδ T cells may have both anti-tumor and tumor-promoting effects. In order to clarify this contradiction, in this review, we summarized the functions of the main subsets of human γδ T cells in how they exhibit their respective anti-tumor or pro-tumor effects in cancer. Then, we reviewed recent γδ T cell-based anti-tumor immunotherapy. Finally, we summarized the existing problems and prospect of this immunotherapy.

Keywords: human; immunity; immunotherapy; tumor; γδ T cells.

Figure 1

Recognition of tumor-associated antigens (TAA) by different γδ T cells. Vδ1TCR could recognize MICA or the complexes of CD1d and TAA; NKR+ (NKG2D and NKp30) Vδ1 T cells could recognize ULBP3 and B7-H6. Besides, Vγ9Vδ2 T cells could also recognize and kill tumors by CD16-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Notably, Vγ4Vδ5TCR could recognize the antigen of epithelial tumor cells, EPCR.

Figure 2

γδ T cells enhance the anti-tumor ability of other immune cells. On the one hand, activated γδ T cells can activate natural killer cells (NK) and dendritic cells (DC), activated DC can further activate γδ T cells. On the other hand, activated γδ T cells can up-regulate the expression of CD36 and enhance their antigen uptake ability after uptake of tumor cell lysates. At the same time, through contact with tumor cells with antibodies, the ability of antigen-presenting cells (APC) is obtained and CD8⁺T cells are activated. In addition, IFN- γ secreted by γδ T cells can up-regulate the expression of CD54 and MHC I molecules in tumor cells, and further enhance the anti-tumor effect of CD8⁺T cells.

Figure 3

Tumor-infiltrating γδ T cells promote the development of tumor. Tumor-infiltrating γδ T cells secrete IL-17 promote the proliferation and metastasis of tumor cells, and recruit myeloid-derived suppressor cells (MDSC) to inhibit the function of CD8⁺T cells. Moreover, tumor-infiltrating γδ T cells directly impaired the function of CD4⁺/CD8⁺T cells and dendritic cells (DC), the aging DC further inhibited CD4⁺/CD8⁺T cells.