Loss of tumor cell MHC Class II drives MAPK-inhibitor insensitivity of BRAF-mutant anaplastic thyroid cancers

Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse BrafV600E-driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita-/- and H2-Ab1-/- ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition. Overall design: We performed whole exome sequencing on mouse cell lines generated from thyroid tumors derived from a genetic engineered anaplastic thyroid cancer mouse model (Tpo-Cre/eYFP/BRaf-CA/Trp53fl/fl; termed Braf-CAV600E/p53) and corresponding normal tissue (mouse tail). The mouse cell lines are B34286 cells, which retained IFN? and trametinib-induced MhcII expression, and two celllines derived from recurrent tumors (B36934 and B36244) which lost MhcII expression in response to IFN? and trametinib treatment. MhcII expression is regulated by the master transcriptional regulator Ciita, which is dependent on BRG1 (SMARCA4), one of the two mutually exclusive ATPases that serve as catalytic subunits of SWI/SNF chromatin remodeling complexes. Upon IFN? stimulation BRG1 displaces EZH2 and SUZ12, key components of the Polycomb Repressor Complex 2 (PRC2), from inter-enhancer regions across the Ciita locus. We tested whether non-synonymous mutations in any of the Swi/Snf genes were present in the two MhcII negative recurrent cell lines (B36244 and B36934) or the MhcII responsive recurrent cells B34286.