The Regulation Of The Expression Of Human Major Histocompatability Class I Molecules On Cancer Cells By Kinases
The major histocompatability complex (MHC) encodes MHC class I molecules which present antigenic peptides to tumor specific CD8 T cells. Druggable kinases may provide the opportunity to enhance expression of MHC class I molecules on tumor cells. However, the regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. The entire human kinome was screened using a pooled shRNA interference-based approach in a human mesothelioma cell line to uncover kinase regulators of MHC-I. Negative and positive regulators of cell surface HLA levels were discovered. A subset of highly scoring positive and negative kinase hits were subsequently validated by additional RNAi, and pharmacologic inhibitors when available. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC class I expression in multiple cancer types. We mapped the pathways responsible for increased MHC class I upon kinase inhibition. Interestingly, inhibition of the MAP Kinase pathway broadly influenced expression of other components of the antigen presentation machinery. Moreover, DDR2 and MINK1 were shown to positively regulate HLA-A*02:01. This had therapeutic relevance, as shown with a therapeutic TCR mimic antibody to a MHC/peptide complex. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. This is the first comprehensive analysis of kinase regulation of the human major histocompatibility complex class I (MHC-class I), a central component of the CD8 T cell-mediated response. Efficient antigen presentation by MHC-I molecules on cancer cells is essential for the success of immunotherapies, including vaccines, checkpoint blockade, adoptive T-cell therapy, and TCR mimic antibodies. We provide a proof of concept of two druggable targets, EGFR and MEK, but expect that these data can broadly influence translational and clinical trial design of targeted therapies combined with immunotherapy.
Antigen Presentation; Immunotherapy; Kinases; Major Histocompatability Complex I; Tumor antigen
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
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