SH3GL1 mediates B7-H3 recycling and enhances the immune escape in non-small cell lung cancer.

Abstract

PurposeThis study aimed to investigate the role of SH3GL1 in regulating B7-H3 expression and its impact on immune escape in non-small cell lung cancer (NSCLC).MethodsSH3GL1 and B7-H3 expression levels were analyzed in The Cancer Genome Atlas datasets and NSCLC cell lines using quantitative reverse transcription polymerase chain reaction and Western blot. SH3GL1 overexpression was performed to assess its effect on B7-H3 expression. Co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were used to confirm the interaction and co-localization of SH3GL1 and B7-H3. Flow cytometry and confocal microscopy were employed to study B7-H3 endocytosis and recycling. The functional impact of SH3GL1 on immune escape was evaluated through T cell co-culture assays and in vivo tumor models.ResultsSH3GL1 and B7-H3 were significantly upregulated in NSCLC clinical samples and cell lines. SH3GL1 overexpression increased B7-H3 protein levels and promoted its recycling to the cell surface by redirecting B7-H3 away from lysosomal degradation. Co-IP and IF confirmed the physical interaction and co-localization of SH3GL1 and B7-H3. In vitro, SH3GL1 overexpression suppressed T cell proliferation, cytotoxicity, and activation while increasing immunosuppressive cytokines. In vivo, SH3GL1 overexpression accelerated tumor growth, increased Treg infiltration, and enhanced B7-H3 expression in tumor tissues.ConclusionSH3GL1 impacts B7-H3 expression and promotes immune escape in NSCLC by enhancing B7-H3 recycling and suppressing T cell function. These findings highlight SH3GL1 as a potential therapeutic target to overcome immune escape in NSCLC.