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

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. To probe into the underlying mechanisms of MhcII loss and attenuated Ciita expression we performed bulk RNA-seq and ATAC-seq. We tested 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). We included one primary (B92) and one recurrent (B36934) cell line after a 96h treatment with DMSO, IFNγ (20ng/ml), trametinib (10nM) or the combination of IFNγ and trametinib in vitro.