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Cancer Immunol Res. 2016 Nov;4(11):936-947. Epub 2016 Sep 28.

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

Author information

1
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.
2
Weill Cornell Medicine, New York, New York.
3
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center New York, New York.
4
Immunology Program, Memorial Sloan Kettering Cancer Center New York, New York.
5
RNAi Core Facility, Memorial Sloan Kettering Cancer Center New York, New York.
6
Howard Hughes Medical Institute, New York, New York.
7
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York. scheinbd@mskcc.org.

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.

PMID:
27680026
PMCID:
PMC5110210
DOI:
10.1158/2326-6066.CIR-16-0177
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

D.A.S. is an inventor of the ESKM technology described in this paper and licensed by Memorial Sloan Kettering Cancer Center to Novartis.

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