Tumor heterogeneity is commonly seen in melanoma patients and a hurdle to effective therapy as illustrated by the “mixed responses” frequently seen in immunotherapy-treated patients. Previously, AXL+ cells were identified to be highly resistant to targeted therapy, whereas more differentiated MITF+ cells responded well to RAF/MEK inhibitors. This study aimed to identify if AXL+ melanoma cells show intrinsic resistance to immunotherapy, and to study if these cells are more resistant than MITF+ subpopulations. Concomitantly, we aimed to validate melanoma subpopulations at protein level and correlate melanoma heterogeneity to immunological pressure. We analyzed the presence of melanoma cell populations in metastatic tissues by scRNAseq and multiplex immunofluorescence, and their phenotypic changes after immunomodulating antibodies or autologous tumor lysate-loaded dendritic cell vaccination. Our data demonstrate large inter patient variability and variable therapy-induced changes, independent of the type of therapy. Treatment with anti-CTLA4 and dendritic cell vaccines did not exclusively select for AXL- cells, as seen for targeted treatment. Immunotherapy-induced changes in the abundance of AXL+ MITF- cells did not correlate with improved survival. MITF+ tumor cells showed a weak inverse correlation with CD8+ T cells, suggesting that these tumor cells may be more immunogenic. Our study highlights that AXL+ cells seem not as resistant to immunotherapy as to targeted treatment. However, immunoreactivity is increased towards MITF-expressing tumor cells, that are therefore likely to respond better to immunotherapy.

ESDR469 - Analyzing resistance of AXL- and/or MITF-expressing melanoma cells to immunotherapy

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.