EGFR-Mutant Lung Adenocarcinoma Cell-Derived Exosomal miR-651-5p Induces CD8+ T Cell Apoptosis via Downregulating BCL2 Expression

<b>Background</b>: The efficacy of programmed cell death 1 (PD-1) or ligand 1 (PD-L1) inhibitors in epidermal growth factor receptor (<i>EGFR</i>)-mutant non-small cell lung cancer (NSCLC) patients is not satisfactory. Studies have indicated that the ratio of CD8+ tumor infiltration lymphocytes (TILs) was associated with immunotherapy efficacy; however, it was significantly lower in <i>EGFR</i>-mutant than wild type patients. The underlying mechanisms need to be studied. <b>Methods</b>: Database analysis, clinical specimens, small RNA sequencing, and single-cell sequencing were used to analyze miRNA expression and immune cell infiltration. Cell co-culture and flow cytometry were conducted to detect immune cell apoptosis. The mouse model was performed to analyze the influence of miR-651-5p antagomirs on the tumor microenvironment. <b>Results</b>: The miR-651-5p was found to be highly expressed in <i>EGFR</i>-mutant lung adenocarcinoma cell-derived exosomes, which could promote CD8+ T cell apoptosis, while the miR-651-5p inhibitor decreased the ratio of PC9-secreted exosomes and induced apoptosis. Mechanistically, the EGFR signaling pathway promoted the expression of miR-651-5p by activating the transcription factor Fos proto-oncogene (FOS) in <i>EGFR</i>-mutant lung adenocarcinoma cell lines. B-cell lymphoma 2 (BCL2) was the target of miR-651-5p, and miR-651-5p could promote T cell apoptosis by inhibiting BCL2 expression. In addition, the miR-651-5p antagomir increased T cell infiltration and enhanced the efficacy of the PD-1 inhibitor treating the <i>EGFR</i>-mutant lung adenocarcinoma humanized mouse model. <b>Conclusions</b>: <i>EGFR</i>-mutant lung adenocarcinoma promotes T cell apoptosis through exosomal miR-651-5p. miR-651-5p antagonists increase immune cell infiltration and enhance the anti-tumor effect of PD-1 inhibitor, suggesting a new combination therapy to improve the efficacy of immunotherapy in <i>EGFR</i>-mutant NSCLC patients.