Abstract 6446: <i>Yap1</i> and CD276/B7-H3: key players in Sex-biased SHH medulloblastoma immune evasion

The molecular mechanisms driving sex disparities in cancer prevalence, progression, and treatment outcomes represent a crucial yet understudied area with significant implications for cancer therapy. Medulloblastoma (MB), exhibits a pronounced sex bias in incidence and survival rates, with males experiencing higher incidence and poorer prognoses compared to females. This study focused on the role of Yap1 in Sonic Hedgehog medulloblastomas (SHH MBs), which revealed an unanticipated sex-biased role of Yap1 in MB immune evasion. Hippo/Yap pathway is one of the top 10 most dysregulated pathways in human cancer. Our in vivo studies uncovered that Yap1 deletion in a spontaneous SHH MB model significantly extended survival, providing genetic evidence that Yap1 is a critical oncogene in MB formation. Notably, Yap1 deletion/inhibition benefitted males, but not females, revealing its sex-biased function for the first time. Integrated multi-omics analyses showed Yap1 is essential for maintaining MB stem/progenitor cells by activating stemness genes (Sox2) and repressing differentiation genes (Neurod1, Zic1/2) in both sexes. However, Yap1 plays a more pivotal role in immune evasion in males, particularly by regulating the immune checkpoint molecule; Cd276/B7-H3. In males, either CD276 blockade or Yap1 deletion reverses T cell suppression. In contrast, in females, CD276 blockade or Yap1 deletion is not sufficient to overcome T cell suppression, and it requires both interventions to activate T cells. Furthermore, our newly discovered transcriptional target gene signatures of YAP1 predict survival in male but not female patients across multiple human cancers, indicating a highly conserved mechanism across species and cancer types. This study highlights sex-specific differences in tumor:immune interactions downstream of YAP1/CD276. In addition, it reveals a novel sex-biased role of YAP1 transcriptional programs, providing molecular entry points for future research on sex differences in immune response. These results underscore the importance of considering sex as a major variable in mechanistic and therapeutic studies involving Yap1 and CD276, with broader implications for targeted cancer therapies. Citation Format: Nourhan Abdelfattah, Sivaraman Natarajan, Han Nhat Tran, Thomas Wong, Jose Maldonado, Rachael McMinimy, Hannah Borland, Shu-hsia Chen, Fernando Camargo, James Olson, Joshy George, Kyuson Yun. Yap1 and CD276/B7-H3: key players in Sex-biased SHH medulloblastoma immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6446.