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Kinase Regulation Of Human MHC Class I Molecule Expression On Cancer Cells

Elliott J Brea, C. Oh, Eusebio Manchado, Sadna Budhu, Ron S. Gejman, George Mo, P. Mondello, James E Han, Casey A. Jarvis, D. Ulmert, Qing Xiang, Aaron Y. Chang, R. Garippa, T. Merghoub, J. Wolchok, N. Rosen, S. Lowe, D. Scheinberg
Published 2016 · Biology, Medicine

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Kinome screens revealed EGFR and MEK as key to reduced MHCI expression on many tumors. FDA-approved inhibitors of these kinases increased surface MHC-I, providing a rationale for clinically testing similar kinase inhibitors with immunotherapies dependent on MHC-I. The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference–based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output–dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936–47. ©2016 AACR.
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