ABSTRACT The Src‐like adaptor 2 (SLA2) functions as a negative regulator of T cell receptor signalling. However, its involvement in the tumour microenvironment (TME) of gastric cancer (GC) remains unexplored. In this study, we found that SLA2 expression was significantly elevated in GC tissues, and a high level of SLA2 was associated with poor prognosis in GC patients. Bioinformatics analyses revealed a close association between SLA2 and TME in GC. Single‐cell RNA sequencing analysis indicated that SLA2 was significantly enriched in CD8 + T cells in GC tissues. Functional validation demonstrated that SLA2 overexpression contributed to the exhaustion of CD8 + T cells by suppressing their proliferation, upregulating the expression of exhaustion markers, reducing the secretion of effector cytokines (IFN‐γ and TNF‐α) and impairing cytotoxic function. SLA2 knockdown in in vitro‐generated exhausted CD8 T cells significantly alleviated T cell exhaustion. Mechanistically, we found that inverse promoter methylation and active histone marks (H3K27ac, H3K4me3 and H3K4me1) may regulate SLA2 expression. Our findings suggest that SLA2 may modulate the TME and promote immune evasion via CD8 + T cell exhaustion in GC.
Zhang et al. (Fri,) studied this question.
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