Kinase regulation of human MHC class i molecule expression on cancer cells Academic Article uri icon

Overview

MeSH Major

  • Insulin Receptor Substrate Proteins
  • PTEN Phosphohydrolase

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.

publication date

  • November 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5110210

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-16-0177

PubMed ID

  • 27680026

Additional Document Info

start page

  • 936

end page

  • 947

volume

  • 4

number

  • 11