Abstract
Abstract New therapies of metastatic melanoma, including BRAF inhibitors, check-point blockade or adoptive T-cell transfer, hold high promise. However, their efficacy remains unsatisfactory. Combination of different modalities offers an opportunity to enhance their effect. We studied mannose 6-phosphate receptor (MPR) previously implicated in synergistic effect of cancer chemotherapy and immunotherapy. Approximately 50% of human melanomas bear the activating mutation V600E in BRAF that can be selectively targeted with BRAF inhibitor PLX4720. We have observed that in vitro treatment of human V600E-positive melanoma cells 451Lu and WM983B leads to a dose-dependent up-regulation of mannose 6-phosphate receptor (MPR) in the cell surface. An increase in cell surface MPR, enhanced recombinant Granzyme B uptake, a requirements for effective combination with immunotherapy. This effect of PLX4720 on MPR expression was reproduced in a mouse model featuring xenograft 451Lu-derived subcutaneous tumors. This effect was limited only to sensitive cell lines, disappearing completely after resistance had been induced by extended treatment with growing doses of the drug. We have previously determined that autophagy has a key role in MPR up-regulation after chemotherapy or radiation therapy. However, in the case of PLX4720, autophagy occurs 1-2 days after the start of the treatment while membrane MPR was up-regulated not early than 3-4 and 10-14 days after the start of the treatment in 451Lu and WM983B cells respectively. In addition, autophagy was present independently of whether the cells were resistant to PLX4720 or not. These data indicate that autophagy was probably not responsible in PLX4720 inducible up-regulation of MPR. We observed a parallel changes in MPR up-regulation and phosphatidylserine (PS) externalization in live melanoma cells. PS and MPR co-localized on cell surface after the treatment with PLX4720. Co-incubation of PLX4720 with PS-specific antibody resulted in an ablation of the subsequent membrane MPR up-regulation. These observations help to explain the synergism between immunotherapy and targeted therapy of melanoma and to design clinical trials. Citation Format: Sergio Lavilla-Alonso, Rolf Brekken, Dmitry Gabrilovich. Up-regulation of mannose 6-phosphate receptor induced by BRAF inhibitor PLX4720 is linked to phosphatidylserine externalization and shows positive effects for combination therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1337. doi:10.1158/1538-7445.AM2015-1337
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