TMIC-45. SEX DIFFERENCES IN YAP1-CD276 EXPRESSION AND FUNCTION IN MEDULLOBLASTOMA IMMUNE EVASION

Abstract

Abstract Sex differences in human diseases are well established; however, little is known about the molecules that link oncogenic events and sex as a biological variable in tumorigenesis and treatment response. Here, we report that Yap1 has a sex-specific role in SHH medulloblastoma (MB) progression and immune suppression. Through integrated genomic, transcriptomic, proteomic, and in vivo transcriptional target analyses, we show that Yap1 concurrently promotes stemness and blocks differentiation of cancer stem cells through at least two distinct but complementary molecular mechanisms. In parallel, Yap1 also promotes immune suppressive tumor microenvironment by directly regulating CD276, Csf1, Igf1, and Igfbp3 transcription and modulating the IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, while Yap1 function is critical for promoting stemness in male and female MB cells, Yap1 plays a more dominant role in promoting immune suppression and Th2 polarization in male MBs. Furthermore, we discovered that a YAP1-target gene, CD276, expression level is higher in female MBs in both mice and humans, demonstrating for the first-time sex differences in expression levels of an immune checkpoint molecule in MB. Functionally, anti-CD276 treatment is more effective in reversing T cell suppression from male MB cells compared to female MB cells, and CD276 expression level stratifies male but not female MB patient survival. Supporting the clinical relevance of our findings, we show that the sex difference in Yap1 function is evolutionarily conserved across multiple tumor types: YAP1 target gene signature predicts poor survival in males but not females in MB, glioblastoma, low-grade glioma, mesothelioma, and hepatocellular carcinoma. In summary, we provide the first evidence of sex-biased expression and function of YAP1 and CD276 in mouse and human cancers and identified the YAP1-CD276 axis as a key contributor to sex differences in immune checkpoint response.