Abstract Medulloblastoma (MB), the most prevalent pediatric brain malignancy, exhibits a notable sex bias in incidence and survival rates. Males have a higher incidence rate across all age groups and have worse prognoses than their females for ages groups over three years old. There is growing evidence that the biological sex is a major variable driving differences in cancer incidence and treatment responses. However, the underlying mechanism is not well understood. Here, we report an unanticipated sex-biased role of the oncogene Yap1 in SHH medulloblastoma. To elucidate whether YAP1 is a cooperating oncogene for SMO-induced SHH MB formation, we genetically deleted Yap1 from a mouse model of SHH MB (Fsmo:GFAP-cre) and observed that Yap1 deletion significantly prolongs survival in males, but not females. Through an integrated multi-omics approach, we demonstrate that YAP1 is required to maintain cancer stem cells in both sexes. In contrast, Yap1 plays a more critical role in regulating genes that promote immune evasion in male MB cells than in female cells. Notably, YAP1 regulates the expression of the immune checkpoint molecule Cd276/B7-H3, which suppresses cytotoxic T cell function. CD276 blockade through a blocking antibody or Yap1 deletion in MB cells is sufficient to reverse T cell suppression in vitro, and Yap1 deletion is sufficient to significantly increase immune infiltrates and T cell activation in vivo. In females, neither CD276 blockade nor Yap1 deletion in MB cells is sufficient to reverse T cell suppression: it required combined inhibition of YAP1 and CD276. We also identified a new set of YAP1 target genes in vivo and these gene signatures predict survival in male but not patients across multiple human cancer types. These findings implicate our findings beyond medulloblastoma and indicate highly conserved dependencies to YAP1 in a sex-biased manner. In conclusion, Yap1 is a critical cooperating oncogene for SMO-induced MB and it promotes MB progression by promoting cancer stem cells and immune suppression.
Abdelfattah et al. (Fri,) studied this question.