Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells.

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.

• Authors: Elliott J Brea, Claire Y Oh, Eusebio Manchado, Sadna Budhu, Ron S Gejman, George Mo, Patrizia Mondello, James E Han, Casey A Jarvis, David Ulmert, Qing Xiang, Aaron Y Chang, Ralph J Garippa, Taha Merghoub, Jedd D Wolchok, Neal Rosen, Scott W Lowe, David A Scheinberg
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 4 Issue 11 Pg. 936-947 (11 2016) ISSN: 2326-6074 [Electronic] United States
• PMID: 27680026 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• HLA-A Antigens
• Histocompatibility Antigens Class I
• Programmed Cell Death 1 Receptor
• RNA, Small Interfering
• Phosphotransferases

Topics

• Animals
• B7-H1 Antigen (metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• HLA-A Antigens (genetics, immunology, metabolism)
• Histocompatibility Antigens Class I (genetics, immunology, metabolism)
• Humans
• Immunotherapy
• MAP Kinase Signaling System
• Melanoma, Experimental
• Mice
• Mice, Transgenic
• Neoplasms (genetics, immunology, metabolism)
• Phosphotransferases (metabolism)
• Programmed Cell Death 1 Receptor (metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)