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Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2016 Nov; Vol. 4 (11), pp. 936-947. Date of Electronic Publication: 2016 Sep 28. - Publication Year :
- 2016
-
Abstract
- The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8 <superscript>+</superscript> 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.<br />Competing Interests: D.A.S. is an inventor of the ESKM technology described in this paper and licensed by Memorial Sloan Kettering Cancer Center to Novartis.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
B7-H1 Antigen metabolism
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
Cell Line, Tumor
Disease Models, Animal
HLA-A Antigens genetics
HLA-A Antigens immunology
HLA-A Antigens metabolism
Histocompatibility Antigens Class I immunology
Histocompatibility Antigens Class I metabolism
Humans
Immunotherapy
MAP Kinase Signaling System
Melanoma, Experimental
Mice
Mice, Transgenic
Neoplasms immunology
Programmed Cell Death 1 Receptor metabolism
RNA Interference
RNA, Small Interfering genetics
Gene Expression Regulation, Neoplastic
Histocompatibility Antigens Class I genetics
Neoplasms genetics
Neoplasms metabolism
Phosphotransferases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 4
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 27680026
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-16-0177