Tumor-derived exosomal tsRNA 3′tiRNA-AlaCGC in promoting fibroblast senescence and Galectin-9 secretion to induce immune tolerance in lung adenocarcinoma
Zhao Guangyin, Yuchen Zhang, Hongyu Zhang, Yifan Guo, Chang Xu, Di Ge, Jie Gu
Abstract
Abstract Given the heterogeneity of the tumor microenvironment (TME), neoadjuvant immunotherapy combined with chemotherapy benefits only a subset of lung adenocarcinoma (LUAD) patients, and the mechanisms of resistance remain unclear. Transfer RNA-derived small RNAs (tsRNAs) are a new class of non-coding RNAs that participate in the remodeling of the TME. Using high-throughput small RNA microarray analysis, we found elevated expression of tsRNA 3′tiRNA-AlaCGC in tumors of LUAD patients resistant to neoadjuvant therapy, and negatively correlated with the poor prognosis in LUAD patients. Furthermore, we discovered that tumor-derived exosome carrying 3′tiRNA-AlaCGC target fibroblasts to induce a senescence-associated secretory phenotype (SASP) by inhibiting FOXO3, and activating the TGF-β/Smad3 pathway, thereby increasing Galectin-9 secretion; both SASP and Galectin-9 induce synthetically dysfunction of cytotoxic CD8 + T cells. In vivo experiments revealed that high expression of 3′tiRNA-AlaCGC led to decrease infiltration and diminished cytotoxic function of CD8 + T cells in tumors of C57BL/6 mice, resulting in anti-PD-L1 therapy resistance. Collectively, our research underscores the immunosuppressive role of 3′tiRNA-AlaCGC in LUAD, offering insights into its molecular traits and aiding personalized treatment strategy development.