HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors.
Pangigadde, Pradeepa N
European Journal of Immunology
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Sottile, R., Pangigadde, P. N., Tan, T., Anichini, A., Sabbatino, F., Trecroci, F., Favoino, E., et al. (2016). HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors.. European Journal of Immunology, 46 (2), 409-419. https://doi.org/10.1002/eji.201445289
The frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B-Raf kinase (BRAF inhibitors, BRAFi). We generated drug-resistant cell variants in vitro from human BRAF-mutant melanoma cell lines MEL-HO, COLO-38, SK-MEL-37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug-resistant cell variants remained susceptible to lysis by IL-2-activated NK cells; and two BRAFi-resistant lines (BRAFi-R) became significantly more susceptible to NK-cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD-L1 upregulation on the drug-resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi-R and parental cells to NK-cell-mediated lysis, antibody-mediated inhibition of PD1-PD-L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi-R melanoma variants thus appears to play a major role in their susceptibility to NK-cell cytotoxicity. These findings suggest that NK-cell-based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors.
NK cell, acquired drug resistance, combination therapy, cytotoxicity, melanoma HLA, B7-H1 Antigen, Cell Line, Tumor, Cytotoxicity, Immunologic, Down-Regulation, Drug Resistance, Neoplasm, HLA-A Antigens, Humans, Imidazoles, Immunotherapy, Adoptive, Interleukin-2, Killer Cells, Natural, Lymphocyte Activation, Melanoma, Oximes, Proto-Oncogene Proteins B-raf, Up-Regulation
This work was sup-ported by the National Institute for Health Research CambridgeBiomedical Research Center Cell Phenotyping Hub and by projectgrants from the Association for International Cancer Research 10–0238 and the Medical Research Council G0900101/1 to FrancescoColucci’s lab and by Associazione Italiana Ricerca Cancro AIRC-IG15521, UICC International Cancer Technology Transfer Fellow-ship and Italian Ministry of Health grant CO-2011-02348049 toEnnio Carbone. Soldano Ferrone was supported P50CA121973awarded by the National Cancer Institute and Klas K¨arre wassupported by The Swedish Cancer Society. Francesco Sabbatinowas supported by a Post-Doctoral Fellowship from the FondazioneUmberto Veronesi
External DOI: https://doi.org/10.1002/eji.201445289
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252645
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/