Although treatment of combination therapy with BRAF and MEK inhibitors in patient with melanoma has shown longer duration of response and higher rate of tumor responses, recurrence of tumor from dual targeted therapy in patients with metastatic melanoma has still remained a challenge to overcome. Here, we provide new therapeutic approaches for BRAF inhibitors-resistant melanoma model that upregulation of mannose-6-phosphate receptor (M6PR) on melanoma by treatment of BRAF inhibitors enhances tumor cytotoxicity level via Granzyme B uptake, which is major component of cytotoxic activity of cytotoxic T lymphocytes (CTLs). Our results demonstrate that treatment of BRAF inhibitor increases M6PR expression temporally in both sensitive and resistant BRAFi melanoma cell lines as well as tumor-bearing mouse models (NOD/SCID). Cytotoxic activity of human melanoma cells by co-culture with patient-derived tumor-infiltrating lymphocytes (TILs) shows correlation with M6PR expression level. Furthermore, treatment of mice bearing resistant tumor with BRAFi enhances the antitumor effect of adaptive TILs transfer. In pilot clinical trials of 16 patients with metastatic melanoma, our results support that administration of BRAF inhibitor to patient shows high level of M6PR expression on tumor tissues. Also, combination treatment of BRAF inhibitor and adaptive cell transfer with patient-derived TILs shows promising clinical results in terms of longer response and tumor-free survival. Taken together, BRAF targeted therapy upregulates M6PR level, which enhances activity of TILs to kill resistant melanoma, providing new therapeutic approaches for patients who have recurrence melanoma.

Note: This abstract was not presented at the conference.

Citation Format: Cigdem Atay, Taekyoung Kwak, Sergio Lavilla-Alonso, Allison Richards, Valerie Moberg, Shari Pilon-Thomas, Michael Schell, Jane L. Messina, Vito W. Rebecca, Gao Zhang, Jeffrey S. Weber, Meenhard Herlyn, Amod A. Sarnaik, Dmitry I. Gabrilovich. BRAF targeting sensitizes resistant melanoma to cytotoxic T cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B41.