γδT细胞识别感染或转化细胞。然而，与αβT细胞不同，γδT细胞是固有样免疫细胞，没有主要的组织相容性复合体限制要求。γδT细胞是肠道上皮内淋巴细胞（IELs）的主要人群，与抗肿瘤免疫反应特别是结直肠癌（CRC）相关。虽然CD8+T细胞在肿瘤微环境（TME）中表现出功能异常甚至衰竭，这有助于肿瘤免疫逃逸，但肿瘤浸润（TI）-γδT细胞是否也存在同样的情况尚不完全了解。在这里，我们试图研究抑制性受体的表达模式和TI-γδT细胞的功能状态，并揭示CRC TME中衰竭TI-γδT细胞的特征。我们证明TI-γδT细胞展示了衰竭表型，并在CRC TME中比TI-CD8+T细胞或NK细胞更严重地显示了功能衰竭。此外，TI-γδT细胞的单细胞RNA测序（scRNA-seq）分析揭示了三个具有显著异质性的衰竭亚群。基于PD-1和TIM-3表达，通过流式细胞术进一步证实了存在三个异质性的衰竭γδT细胞（Tex）人群，包括Texprog，Textran和Texterm。最后，我们揭示了c-Maf不仅通过上调抑制性受体促进了γδT细胞的衰竭，而且还参与了CD8+T细胞和NK细胞的衰竭。在CRC患者中，c-Maf也可能是γδT细胞衰竭的重要贡献者。这些发现表明TI-γδT细胞在CRC TME中表现出表型和功能衰竭。衰竭TI-γδT细胞的显著特征有助于理解γδT细胞衰竭与肿瘤发展和病因的机制和关联。©2023年国际癌症杂志。由约翰威利和苏司有限公司代表UICC出版。

The 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.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.