Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells.
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.
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.|Weill Cornell Medicine, New York, New York.
Elliott J
EJ
Brea
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.|Weill Cornell Medicine, New York, New York.
Claire Y
CY
Oh
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center New York, New York.
Eusebio
E
Manchado
Immunology Program, Memorial Sloan Kettering Cancer Center New York, New York.
Sadna
S
Budhu
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.|Weill Cornell Medicine, New York, New York.
Ron S
RS
Gejman
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.
George
G
Mo
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.
Patrizia
P
Mondello
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.|Weill Cornell Medicine, New York, New York.
James E
JE
Han
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.
Casey A
CA
Jarvis
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.
David
D
Ulmert
RNAi Core Facility, Memorial Sloan Kettering Cancer Center New York, New York.
Qing
Q
Xiang
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.|Weill Cornell Medicine, New York, New York.
Aaron Y
AY
Chang
RNAi Core Facility, Memorial Sloan Kettering Cancer Center New York, New York.
Ralph J
RJ
Garippa
Immunology Program, Memorial Sloan Kettering Cancer Center New York, New York.
Taha
T
Merghoub
Weill Cornell Medicine, New York, New York.|Immunology Program, Memorial Sloan Kettering Cancer Center New York, New York.
Jedd D
JD
Wolchok
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York.|Weill Cornell Medicine, New York, New York.
Neal
N
Rosen
Weill Cornell Medicine, New York, New York.|Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center New York, New York.|Howard Hughes Medical Institute, New York, New York.
Scott W
SW
Lowe
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York, New York. scheinbd@mskcc.org.|Weill Cornell Medicine, New York, New York.
David A
DA
Scheinberg
D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D020935:MAP Kinase Signaling System; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; D010770:Phosphotransferases
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