Targeting ABL kinases overcomes melanoma immune evasion following resistance to MAPK inhibition

Abstract

MAPK inhibitors (MAPKi) are important treatment options for some patients with metastatic melanoma; however, resistance inevitably develops in the vast majority of cases (>70%). Here, using immune-proficient mouse models, single-cell RNA sequencing, flow cytometry, and datasets from patients treated with MAPKi, we demonstrate that ABL kinases (ABL1/2) promote MAPKi resistance not only by impacting intracellular signaling but also by driving secretion of chemokines that suppress the immune microenvironment. Targeting ABL1/2 reduces chemokine secretion by melanoma cells, prevents immunosuppressive myeloid-derived suppressor cell (MDSC) infiltration, and promotes accumulation of cytotoxic CD8+ T cells. Depletion of MDSCs prevents resistance, and depletion of CD8+ T cells or re-expression of chemokines blocks ABL inhibitors from preventing resistance. Importantly, CXCR2 receptor ligand expression and ABL1/2 activity are reduced in patients who respond to treatment but increased during resistance. Thus, the dual role of ABL1/2 in proliferation/survival and immune suppression makes them attractive targets for potential treatments. Although MAP kinase inhibitors (MAPKi) can initially reduce tumour burden in metastatic melanoma, resistance to treatment often occurs. Here, the authors demonstrate that concomitant treatment with ABL kinase inhibitors overcomes tumour resistance to MAPKi by promoting the accumulation of cytotoxic T lymphocytes and inhibiting the infiltration of immunosuppressive cells.