Journal Article

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

Ghossein, Ronald A., Qin, Tianyue, Koche, Richard P., Jin, Jian, Sherman, Eric J., Im, Soo-Yeon, Greenberg, Jillian, Knauf, Jeffrey A., Fagin, James A., Socci, Nicholas D., Xu, Bin, Ho, Alan L., French, Jena D., de Stanchina, Elisa, Boucai, Laura, Krishnamoorthy, Gnana P., Tiedje, Vera

2025

Overview

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 antitumor response. We found that mouse BrafV600E-driven anaplastic thyroid cancers (ATCs) responded markedly to the RAF plus MEK inhibitors dabrafenib and trametinib (dab/tram) and that this was associated with upregulation of MhcII in cancer cells and increased CD4+ T cell infiltration. A subset of recurrent tumors lost MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved IFN-γ signal transduction, which could be rescued by EZH2 inhibition. Orthotopically implanted Ciita-/- and H2-Ab1-/- ATC cells into immune-competent mice became unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+, T cells also abrogated the 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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antigen presentation / Antigens / Antimitotic agents / Antineoplastic agents / Antitumor activity / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - pathology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - pathology / Cell activation / Cell Line, Tumor / Cellular signal transduction / CIITA protein / Cytotoxicity / Drug Resistance, Neoplasm - genetics / Histocompatibility Antigens Class II - genetics / Histocompatibility Antigens Class II - immunology / Humans / Imidazoles - pharmacology / Kinases / Lymphocytes / Lymphocytes T / Major histocompatibility complex / MAP kinase / MAP Kinase Signaling System - drug effects / MAP Kinase Signaling System - genetics / MEK inhibitors / Melanoma / Metastases / Mice / Mice, Knockout / Mutants / Mutation / Neoantigens / Nuclear Proteins - genetics / Nuclear Proteins - immunology / Oximes - pharmacology / Peptides / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - genetics / Pyridones - pharmacology / Pyrimidinones - pharmacology / Raf protein / Signal transduction / T cells / Thyroid / Thyroid cancer / Thyroid Carcinoma, Anaplastic - drug therapy / Thyroid Carcinoma, Anaplastic - genetics / Thyroid Carcinoma, Anaplastic - immunology / Thyroid Carcinoma, Anaplastic - pathology / Thyroid Neoplasms - drug therapy / Thyroid Neoplasms - genetics / Thyroid Neoplasms - immunology / Thyroid Neoplasms - pathology / Trans-Activators - genetics / Trans-Activators - immunology / Tumors