Tumor‐infiltrating gamma delta T‐cells reveal exhausted subsets with remarkable heterogeneity in colorectal cancer

Abstract

AbstractThe γδT‐cells recognize infected or transformed cells. However, unlike αβT‐cells, γδT‐cells are innate‐like immune cells, with no major histocompatibility complex restriction requirements. γδT‐cells are the main population of intestinal intraepithelial lymphocytes (IELs) and are associated with the antitumor immune response, particularly in colorectal cancer (CRC). Although CD8+T‐cells exhibit dysfunction and even exhaustion in the tumor microenvironment (TME), which contributes to tumor immune escape, whether the same applies to tumor‐infiltrating (TI)‐γδT‐cells is not completely understood. Here, we sought to investigate the expression pattern of inhibitory receptors and functional state of TI‐γδT‐cells, and reveal the features of exhausted TI‐γδT‐cells in the CRC TME. We demonstrated that TI‐γδT‐cells exhibited exhaustion phenotypes and displayed more severe functional exhaustion than TI‐CD8+T‐cells or NK‐cells in the TME of CRC. In addition, scRNA‐seq analysis of TI‐γδT‐cells revealed three exhausted subsets with remarkable heterogeneity. The presence of three heterogeneous exhausted γδT‐cell (Tex) populations, including Texprog, Textran and Texterm were further confirmed by flow cytometry, on the basis of PD‐1 and TIM‐3 expression. Finally, we revealed that c‐Maf not only contributed to γδT‐cell exhaustion via upregulation of inhibitory receptors, but also involved in the exhaustion of CD8+T and NK‐cells. c‐Maf may also be an important contributor to γδT‐cell exhaustion in CRC patients. These findings indicated that TI‐γδT‐cells exhibit phenotypic and functional exhaustion in the CRC TME. The revealed features of exhausted TI‐γδT‐cells may provide help for understanding the mechanisms and the association of γδT‐cell exhaustion with tumor development and pathogenesis.