journal contribution
posted on 2023-04-04, 01:41 authored by Zexian Zeng, Shengqing Stan Gu, Nofal Ouardaoui, Carly Tymm, Lin Yang, Cheryl J. Wong, Dian Li, Wubing Zhang, Xiaoqing Wang, Jason L. Weirather, Scott J. Rodig, F. Stephen Hodi, Myles Brown, X. Shirley Liu Supplementary Data from Hippo Signaling Pathway Regulates Cancer Cell–Intrinsic MHC-II Expression
Funding
Breast Cancer Research Foundation (BCRF)
National Institutes of Health (NIH)
Sara Elizabeth O'Brien Trust (O'Brien Trust)
History
ARTICLE ABSTRACT
MHC-II is known to be mainly expressed on the surface of antigen-presenting cells. Evidence suggests MHC-II is also expressed by cancer cells and may be associated with better immunotherapy responses. However, the role and regulation of MHC-II in cancer cells remain unclear. In this study, we leveraged data mining and experimental validation to elucidate the regulation of MHC-II in cancer cells and its role in modulating the response to immunotherapy. We collated an extensive collection of omics data to examine cancer cell–intrinsic MHC-II expression and its association with immunotherapy outcomes. We then tested the functional relevance of cancer cell–intrinsic MHC-II expression using a syngeneic transplantation model. Finally, we performed data mining to identify pathways potentially involved in the regulation of MHC-II expression, and experimentally validated candidate regulators. Analyses of preimmunotherapy clinical samples in the CheckMate 064 trial revealed that cancer cell–intrinsic MHC-II protein was positively correlated with more favorable immunotherapy outcomes. Comprehensive meta-analyses of multiomics data from an exhaustive collection of data revealed that MHC-II is heterogeneously expressed in various solid tumors, and its expression is particularly high in melanoma. Using a syngeneic transplantation model, we further established that melanoma cells with high MHC-II responded better to anti–PD-1 treatment. Data mining followed by experimental validation revealed the Hippo signaling pathway as a potential regulator of melanoma MHC-II expression. In summary, we identified the Hippo signaling pathway as a novel regulator of cancer cell–intrinsic MHC-II expression. These findings suggest modulation of MHC-II in melanoma could potentially improve immunotherapy response.
