Abstract 1819: The immunosuppressive role of YAP1 on the tumor immune microenvironment

Abstract Background and aims: Lung adenocarcinoma (LUAD), the most prevalent histologic subtype of non-small cell lung cancer, is one of the most fatal malignancies. Despite the reported direct link between Hippo pathway and suppression of CD8+ and CD4+ T cell function in the context of cancer, its dynamic modulation and tumor microenvironment (TME) in LUAD remain unclear. We aim to investigate the correlation between YAP1 (a major component of Hippo signalling pathway), TME, and the overall survival of patients with LUAD. Methods: The SsGSEA, CIBERSORT, and ESTIMATE algorithms were applied, and gene set enrichment analysis (GSEA) was conducted to screen Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways between patients with LUAD expressing low and high levels of YAP1 utilizing data downloaded from The Cancer Genome Atlas database. Flow cytometry was performed to detect the immune cell infiltration in LUAD mice model and patients. Western blot and qRT-PCR were used to investigate the mRNA and protein expression of YAP1 from mice model and patients. Results: In this study, we demonstrated that YAP1 was negatively related to activated CD4/CD8 T cells and positively linked to immature dendritic cell, Tregs, and MDSC in 497 LUAD patients from TCGA, while it was not associated with signatures of 37 immunoregulatory and effector molecules, 37 cytokines. GSEA revealed that the high YAP1 group was not enriched in GO terms and KEGG pathways related to the immune response. However, high level of YAP1 positively correlated to immune score. In LUAD mice model, YAP1 knockout was associated with a reduced Treg cell intratumoural representation, and with higher production of interferon-γ and tumour necrosis factor by CD8+ and CD4+ effector cells (markers of increased cytotoxic activity). Moreover, YAP1 level was negatively related to overall survival in patients. Conclusion: YAP1 expression within the TME might be useful as a predictive biomarker for immune response and a novel immunotherapeutic prognostic biomarker for LUAD. Citation Format: Ling-Ling Zhu, Jiewei Liu, Jiang Chen. The immunosuppressive role of YAP1 on the tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1819.