IMPACT OF BRAF INHIBITORS ON THE IMMUNE MICROENVIRONMET IN MELANOMA

FLORENCIA VIEGAS; GABRIELA GREMEL; ANABELA CUTINE; YAMIL DAMIÁN MAHMOUD; SANTIAGO MÉNDEZ-HUERGO; JUAN CARLOS STUPIRSKI; ROSA MORALES; SABRINA GATTO; JUAN MANUEL PÉREZ SÁEZ; KARINA V. MARIÑO; RICHARD MARAIS; GABRIEL ADRIÁN RABINOVICH; MARÍA ROMINA GIROTTI

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

SAIC, SAI

Abstract: BRAF is mutated in 50% of melanoma patients. BRAF is a component of the RAS/RAF/MEK/ERK pathway and BRAF or MEK inhibitors increase progression-free and overall survival in BRAF- mutant patients. However, most patients relapse with acquired resistance and ~20% of patients present intrinsic resistance. Preclinical and translational studies have shown that targeting the RAS/BRAF/MEK/ERK pathway has effects on the expression of immunomodulatory pathways. Macrophages are key players within the tumor microenvironment and their functional profiles control responses to a variety of therapies. Whereas M1 macrophages efficiently present antigens to T cells and promote tumor destruction, M2 macrophages promote tumor progression, immune evasion and angiogenesis. Most patients who develop resistance to targeted therapies derive little benefit from anti-CTLA-4 and anti PD-1 based immunotherapies. Our preliminary findings based on glycophenotyping, transcriptomics data analysis, western blotting and functional studies show changes in the galectin/glycan axis in melanoma resistance to BRAF inhibitors (BRAFi). Particularly we found in patient tumor biopsies collected prior to and on/following treatment with the BRAFi vemurafenib that M2 macrophage density (as defined by CD163+/CD68+) was increased after treatment (p=0.02, n=7). Initial in vitro data supports a direct interaction between tumor cells and peripheral blood monocytes, with BRAF inhibitor-resistant cells driving monocyte differentiation towards a CD163+ phenotype. Moreover, the glycosylation profile of BRAFi resistant cells show an increase in asialo core 1 O-glycans and augmented levels of polylactosamines. Additionally, resistance to BRAFi decreases α(2,6) sialylation levels (n=3, p