VEMURAFENIB-RESISTANT MELANOMA CELLS INDUCE AN IMMUNOSUPPRESSIVE RESPONSE IN MACROPHAGES

MONS JOHINNA; PEREZ CELIA; FALCÓN CRISTIAN ROBERTO; CUELLO ORLANDI SERGIO FEDERICO; SANGIACOMO RUIZ MERCEDES L; ALVAREZ SERGIO

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2023

Sociedad Argentina de investigación Clínica

Melanoma is the most aggressive form of skin cancer. Althoughtargeted therapy with BRAF and MEK inhibitors (BRAFi/MEKi) hasshown an impressive success, the occurrence of resistance and relapsereduces its efficacy. Many reports have established that the tumormicroenvironment and infiltration of different immune cells havea crucial role in cancer progression and resistance. In that sense,expression of the immune checkpoint (IC) Tim-3 and its ligandGalectin 9 (Gal 9) are linked to immune exhaustion. The aim of thiswork was to elucidate how Vemurafenib (Vem, BRAFi) resistanceaffects Gal 9 expression in melanoma cells, thus modulating Tim-3 expression in macrophages. The expression of Gal 9 and Tim-3was evaluated in sensitive and Vem-resistant A375 melanoma cells(A375S and A375R respectively) by RT-qPCR. Resistance was associatedwith increased expression of Gal 9 and other IC ligandssuch as PD-L1 and PD-L2. On the other hand, Tim-3 expressionwas evaluated by treating PMA-differentiated THP-1 cells with conditionedmedia (CM) derived from A375S and A375R cells. Remarkably,while differentiated macrophages exposed to CM from A375Rcells showed an M2-like profile, CM from both cell types induced thedown-regulation of Tim-3. To further study the regulation of theseproteins, we performed a bioinformatic analysis using the open accessweb server GEPIA2. In sílico data show a higher expressionof both Tim-3 and Gal 9 in melanoma compared to healthy tissue.Altogether, our results indicate that resistance to BRAFi increasesGal 9 expression in melanoma and induces an immunosuppressiveresponse by macrophages. Furthermore, we suggest that secretionof Gal 9 by melanoma cells may modulate the expression of Tim-3in macrophages.