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

被引:138
作者
Brea, Elliott J. [1 ,2 ]
Oh, Claire Y. [1 ,2 ]
Manchado, Eusebio [3 ]
Budhu, Sadna [4 ]
Gejman, Ron S. [1 ,2 ]
Mo, George [1 ]
Mondello, Patrizia [1 ]
Han, James E. [1 ,2 ]
Jarvis, Casey A. [1 ]
Ulmert, David [1 ]
Xiang, Qing [5 ]
Chang, Aaron Y. [1 ,2 ]
Garippa, Ralph J. [5 ]
Merghoub, Taha [4 ]
Wolchok, Jedd D. [2 ,4 ]
Rosen, Neal [1 ,2 ]
Lowe, Scott W. [2 ,3 ,6 ]
Scheinberg, David A. [1 ,2 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA
[2] Weill Cornell Med, New York, NY USA
[3] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA
[4] Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA
[5] Mem Sloan Kettering Canc Ctr, RNAi Core Facil, 1275 York Ave, New York, NY 10021 USA
[6] Howard Hughes Med Inst, New York, NY USA
关键词
T-CELL; MALIGNANT MESOTHELIOMA; CTLA-4; BLOCKADE; DOWN-REGULATION; MEK INHIBITION; HLA-A; COMBINATION; BRAF; MELANOMA; PD-1;
D O I
10.1158/2326-6066.CIR-16-0177
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2016 AACR.
引用
收藏
页码:936 / 947
页数:12
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