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Abstract：
Although γδ T cells are known to participate in immune dysregulation in solid tumors, their relevance to human microsatellite-stable (MSS) colorectal cancer (CRC) is still undefined. Here, using integrated gene expression analysis and T cell receptor sequencing, we characterized γδ T cells in MSS CRC, with a focus on Vδ1 + T cells. We identified Vδ1+ T cells with shared motifs in the third complementarity-determining region of the δ-chain, reflective of antigen recognition. Changes in gene and protein expression levels suggested a dysfunctional effector state of Vδ1+ T cells in MSS CRC, distinct from Vδ1+ T cells in microsatellite-instable (MSI). Interaction analysis highlighted an immunosuppressive role of fibroblasts in the dysregulation of Vδ1+ T cells in MSS CRC via the TIGIT-NECTIN2 axis. Blocking this pathway with a TIGIT antibody partially restored cytotoxicity of the dysfunctional Vδ1 phenotype. These results define an operative pathway in γδ T cells in MSS CRC.
摘要：
尽管已知γδT细胞参与实体瘤的免疫失调,它们与人类微卫星稳定(MSS)结直肠癌(CRC)的相关性仍不明确.这里,使用整合的基因表达分析和T细胞受体测序，我们表征了MSSCRC中的γδT细胞，重点研究Vδ1+T细胞。我们确定了在δ链的第三个互补决定区中具有共享基序的Vδ1T细胞，反映抗原识别。基因和蛋白质表达水平的变化提示MSSCRC中Vδ1+T细胞的功能失调的效应状态，与微卫星不稳定(MSI)的Vδ1+T细胞不同。相互作用分析强调了成纤维细胞通过TIGIT-NECTIN2轴在MSSCRC中Vδ1+T细胞失调中的免疫抑制作用。用TIGIT抗体阻断该途径部分恢复了功能失调的Vδ1表型的细胞毒性。这些结果定义了MSSCRC中γδT细胞的操作途径。
