BRAF targeting sensitizes resistant melanoma to cytotoxic T cells

Purpose: BRAF and MEK inhibitors (BRAFi, MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAF^V600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T cells therapy (ACT) in melanoma resistant to BRAFi. Experimental design: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as PDXs derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT. Results: Herein we report that in human melanoma cell lines senstitive and resistant to BRAFi and in PDXs from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient up-regulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TIL. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TIL demonstrated significant increase of M6PR expression on tumors during vemurafenib treatment. Conclusions: BRAF targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF resistant disease.

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