Kinase regulation of human MHC class I molecule expression on cancer cells

EJ Brea, CY Oh, E Manchado, S Budhu… - Cancer immunology …, 2016 - AACR
EJ Brea, CY Oh, E Manchado, S Budhu, RS Gejman, G Mo, P Mondello, JE Han, CA Jarvis
Cancer immunology research, 2016AACR
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 …
Abstract
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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