Abstract 3037: Sex-specific differences in Yap1 and Cd276 function and expression regulate medulloblastoma progression and immune evasion

Abstract

Abstract Unveiling the molecular mechanisms underlying sex-specific differences in cancer initiation, progression and treatment outcomes will provide novel insights that will advance cancer research and clinical care. This study highlights an unexpected, sex-biased role of the oncogene Yap1 in SHH medulloblastoma (MB). We discovered that Yap1 deletion in SmoM2-driven SHH MB significantly prolongs survival in male but not female mice. Using an integrated multi-omics approach, we show that YAP1 promotes cancer stem cell maintenance through concurrent transcriptional activation of stemness genes, such as Sox2, and repression of differentiation genes such as NeuroD1 and Zic1/2. Interestingly, while Yap1 is essential for maintaining cancer stem cells in both sexes, it plays a more critical role in immune evasion in males. Specifically, YAP1 regulates the expression of an immune checkpoint molecule Cd276 to suppress T cell function. Blocking CD276 or deleting Yap1 is sufficient to significantly reverse T cell suppression in males but not females. Furthermore, YAP1 direct targets of transcriptional regulation, including CD276, predicts survival in male but not female patients across multiple human cancers, suggesting that our findings have broader implications beyond medulloblastomas and is conserved across species. This study provides compelling evidence for male-biased susceptibility to Yap1 inhibition and uncovers the YAP1-CD276 axis as a sexually diverse pathway in T cell suppression in tumors. Citation Format: Nourhan Abdelfattah, Sivaraman Natarajan, Han Nhat Tran, Jose Maldonado, Rachael McMinimy, Hannah Borland, Shu-hsia Chen, Fernando Camargo, James Olson, Joshy George, Kyuson Yun. Sex-specific differences in Yap1 and Cd276 function and expression regulate medulloblastoma progression and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3037.