Prior targeted therapy treatment and cellular composition modulate the effects of Axl inhibition on myeloid cells in the human in vitro melanoma tumor microenvrionment

Axl has gained momentum as a promising target in cancer therapy due to its contribution to both cancer progression and immunosuppression. While pre-clinical studies in mice have demonstrated its potential as a dual target - to be both tumoricidal and immunostimulatory - clinical trials have reported mixed results. We built a human in vitro model system to understand how prior standard-of-care treatment in the context of melanoma impacts the effects of the small molecule Axl inhibitor bemcentinib on myeloid cells in the tumor microenirnoment. In our previous work we reported differences in macrophage state and activity primarily resulted from whether the melanoma cells they were co-cultured with had prior trametinib + dabrafenib treatment, and that this then impacted the macrophage resposne to Axl inhibition. We also showed that the addition of donor-matched dendritic cells to the in vitro system resulted in a dampened macrophage response. In this current work, we generated single-cell RNA-sequencing data to understand the changes in cell signaling that underlie our previously reported observations.