1224 AhR regulates the efferocytosis and polarization of tumor-associated macrophages through ALKAL1-mediated MerTK activation and promotes melanoma progression

Macrophages in the tumor microenvironment engulf apoptotic cells through myeloid-epithelial-reproductive tyrosine kinase (MerTK)-mediated efferocytosis, and further polarized towards an M2 phenotype. However, regulatory mechanism of efferocytosis polarization tumor-associated macrophages (TAMs) remains unclear. Here, we performed single-cell RNA sequencing patients with melanoma identified a population MerTK+ (MerTK+ Mac), which was closely associated stages response to anti-PD-1 immunotherapy. Moreover, aryl hydrocarbon receptor (AhR) highly expressed Mac promoted MerTK-mediated phagocytosis. In addition, ChIP analysis showed that ALKAL1, ligand for kinase, target gene AhR. MerTK phosphorylation activation dependent on AhR-mediated transcription thereby resulting enhanced phenotype elevated expression Arg1, CD206 PD-L1. Both AhR ALKAL1 inhibitor could suppress inhibit macrophages, therefore repolarizing into M1 iNOS, CD80/86 increased production IL-6, IL-1β TNF-α vitro. Most importantly, adoptive transfer tissues either macrophage-depleted wildtype or Lyz2cre/+Ahrfl/fl mice accelerate growth vivo. Furthermore, also demonstrated specifically targeted delivery M2-TAMs mannosylated micelles progression tumor-bearing mouse models. Blocking AhR-MerTK signaling improved efficacy anti-PD-L1 therapy. Collectively, our study revealed TAMs, thus furthering understanding macrophage providing new strategies immunotherapy melanoma.