2024 World Conference on Lung Cancer (WCLC) - Posters-P1.02D.02 Tumor-Derived Exosomal tsRNA 3’ tiRNA-AlaCGC Promotes Immune Tolerance by Inducing Fibroblast Senescence in LUAD

P1.02D.02 Tumor-Derived Exosomal tsRNA 3’ tiRNA-AlaCGC Promotes Immune Tolerance by Inducing Fibroblast Senescence in LUAD

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The study investigates the role of tumor-derived exosomal tsRNA 3' tiRNA-AlaCGC in lung adenocarcinoma (LUAD), particularly in relation to its impact on immune tolerance and resistance to immunotherapy. TsRNAs are small RNA molecules that can influence the tumor microenvironment (TME) by affecting mRNA stabilization, and in this study, their role in LUAD immunotherapy resistance was explored.<br /><br />Using a high-throughput Arraystar Small RNA microarray, the researchers examined the correlation between tsRNA and immunotherapy resistance in a cohort undergoing neoadjuvant chemotherapy combined with immunotherapy. They focused on the expression, clinical relevance, and biological functions of 3'tiRNA-AlaCGC in LUAD. A variety of techniques, including RNA sequencing and cytokine microarrays, were employed to scrutinize the role of this RNA in immune cells and fibroblasts, as well as the mechanisms leading to immune resistance.<br /><br />The results demonstrated that 3'tiRNA-AlaCGC was significantly elevated in patients with progressive disease compared to those with partial response, correlating with poor prognosis and reduced CD8 T cell presence. Although changing the levels of 3'tiRNA-AlaCGC did not directly impact LUAD cell proliferation or tumor size in immunodeficient mice, it led to an increase in fibroblast senescence and senescence-associated secretory phenotype (SASP). This was achieved through decreased expression of FOXO3, ultimately suppressing CD8 T cell function in the TME.<br /><br />The study concludes that 3'tiRNA-AlaCGC in LUAD cells, secreted via exosomes, induces fibroblast senescence, leading to decreased anti-tumor capacity of CD8 T cells and resistance to anti-PD-L1 immunotherapy. Thus, targeting 3'tiRNA-AlaCGC may present a novel strategy for enhancing immunotherapy efficacy in LUAD patients.

Asset Subtitle

Yuchen Zhang

Meta Tag

Speaker Yuchen Zhang

Topic Tumor Biology – Preclinical Biology

Keywords

lung adenocarcinoma

tumor-derived exosomal tsRNA

3'tiRNA-AlaCGC

immune tolerance

immunotherapy resistance

tumor microenvironment

CD8 T cells

fibroblast senescence

anti-PD-L1 immunotherapy

neoadjuvant chemotherapy