HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors.

Abstract

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.

• Authors: Rosa Sottile, Pradeepa N Pangigadde, Thomas Tan, Andrea Anichini, Francesco Sabbatino, Francesca Trecroci, Elvira Favoino, Laura Orgiano, James Roberts, Soldano Ferrone, Klas Kärre, Francesco Colucci, Ennio Carbone
• Journal: European journal of immunology (Eur J Immunol) Vol. 46 Issue 2 Pg. 409-19 (Feb 2016) ISSN: 1521-4141 [Electronic] Germany
• PMID: 26564811 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• B7-H1 Antigen
• HLA-A Antigens
• Imidazoles
• Interleukin-2
• Oximes
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• dabrafenib

Topics

• B7-H1 Antigen (genetics, metabolism)
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• Down-Regulation
• Drug Resistance, Neoplasm
• HLA-A Antigens (genetics, metabolism)
• Humans
• Imidazoles (administration & dosage, pharmacology)
• Immunotherapy, Adoptive (methods)
• Interleukin-2 (metabolism)
• Killer Cells, Natural (immunology)
• Lymphocyte Activation
• Melanoma (immunology, therapy)
• Oximes (administration & dosage, pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors)
• Up-Regulation