MerTK+ macrophages promote melanoma progression and immunotherapy resistance through AhR-ALKAL1 activation
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux prélevés sur des patients atteints d'un mélanome, cette étude met en évidence un mécanisme par lequel les macrophages MerTK+ favorisent la progression tumorale et la résistance aux immunothérapies via l'activation de la voie de signalisation de l'axe "récepteur d'aryl hydrocarbone - ligand ALKAL1"
Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK+ macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK+ macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK+ macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti–programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK+ macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.