Aberrant apoptotic machinery confers melanoma dual resistance to BRAFV600E inhibitor and immune effector cells: immunosensitization by a histone deacetylase inhibitor

American journal of clinical and experimental immunology

Ali R Jazirehi¹ 

关键词: Vemurafenib;    MAPK;    BRAFV600E kinase inhibitor;    apoptosis;    immunotherapy;    signal transduction;    adoptive cell transfer;    HDACi;    SAHA;    gene expression;    sensitization;    melanoma;    NK cells;    TCR transgenic CTL;   

DOI  :  

学科分类：过敏症与临床免疫学

来源: e-Century Publishing Corporation

【 摘 要 】

BRAFV600E-inhibitors (BRAFi; e.g., vemurafenib) and modern immune-based therapies such as PD-1/PD-L1 and CTLA-4 checkpoints blockade and adoptive cell transfer (ACT) have significantly improved the care of melanoma patients. Having these two effective (BRAFi and immunotherapy) therapies raises the question whether there is a rational biological basis for using them in combination. We developed an in vitro model to determine whether tumor resistance mechanisms to a small molecule inhibitor of a driver oncogene, and to cytotoxic T lymphocyte (CTL)- and natural killer (NK) cell-delivered apoptotic death signals were exclusive or intersecting. We generated melanoma sublines resistant to BRAFi vemurafenib and to CTL recognizing the MART-1 melanoma antigen. Vemurafenib-resistant (VemR) sublines were cross-resistant to MART CTL and NK cells indicating that a common apoptotic pathway governing tumor response to both modalities was disrupted. Pretreatment of VemR melanomas with a histone deacetylase inhibitor (HDACi) restored sensitivity to MART CTL and NK apoptosis by skewing the apoptotic gene programs towards a proapoptotic phenotype. Our in vitro findings suggest that during the course of acquisition of BRAFi resistance, melanomas develop cross-resistance to CTL- and NK-killing. Further, aberrant apoptotic pathways, amenable by an FDA-approved chromatin remodeling drug, regulate tumor resistance mechanisms to immune effector cells. These results may provide rational molecular basis for further investigations to combine these therapies clinically.

【 授权许可】

CC BY-NC