AXL tyrosine kinase inhibition rescues immune checkpoint blockade-resistant melanoma in a tumor microenvironment-dependent fashion

Melanomas resistant to immune checkpoint blockade (ICB) therapies are frequently characterized by having a tumor-immune microenvironment (TiME) enriched with immunosuppressive tumor associated macrophages (TAMs). AXL tyrosine kinase is an emerging molecular target implicated in aggressive behavior by multiple cancers and both immunostimulatory and immunosuppressive functions of TAMs, however its role as a therapeutic target in melanoma has been poorly defined. Here, we define the relevance of AXL in melanoma with focus on efficacy of AXL-targeted therapy to restore sensitivity to anti-PD-1 therapy, shift TAM profiles, and augment anti-tumor immune responses in a TiME-specific context. We first demonstrated that the AXL+ tumor cell populations within melanoma are small, with TAMs representing the overwhelming source of AXL expression and activity. AXL inhibition effectively treated ICB-resistant melanoma and synergized with anti-PD-1 therapy in vivo; however, results were TAM-dependent. In vitro and in vivo, AXL inhibition in macrophages resulted in a powerful immunostimulatory reprogramming with net effect of disrupting checkpoint interactions in tumors. These results indicate that use of AXL as a selective biomarker or AXL inhibition as a therapeutic strategy to restore ICB responses may be cell-type or TiME-specific. Our data supports the modulation of TAM-enriched environments to enhance responses to immunotherapy that may facilitate future precise tailoring of therapies for refractory melanoma. Statement of SignificanceThis study investigates the macrophage-driven impact of AXL tyrosine kinase inhibition in ICB-resistant melanoma. AXL inhibition reduces TAMs in vivo and shifts immunosuppressive TAMs to immunostimulatory functions to improve response to ICB but may require immunostimulatory TAM-environments for maximal effect. These findings support the further exploration of AXL-targeting in TAMs for overcoming ICB resistance in precision melanoma treatment.