Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy
Background: Tumor heterogeneity is a hurdle to effective therapy, as illustrated by the ‘mixed responses’ frequently seen in immunotherapy-treated patients. Previously, AXL+ tumor cells were identified to be highly resistant to targeted therapy, whereas more differentiated MITF+ tumor cells do respo...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-12-01
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| Series: | Immuno-Oncology and Technology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S259001882400306X |
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| Summary: | Background: Tumor heterogeneity is a hurdle to effective therapy, as illustrated by the ‘mixed responses’ frequently seen in immunotherapy-treated patients. Previously, AXL+ tumor cells were identified to be highly resistant to targeted therapy, whereas more differentiated MITF+ tumor cells do respond to RAF and MEK inhibitors. Patients and methods: In this study, we analyzed tumor heterogeneity and explored the presence of the previously described AXL+ or MITF+ melanoma subpopulations in metastatic tissues by NanoString gene expression analysis, single-cell RNA sequencing and in situ multiplex immunofluorescence. Furthermore, we analyzed how these subpopulations correlate with immunological pressure and response to immunotherapy by immunomodulating antibodies or autologous tumor lysate-loaded dendritic cell vaccination. Results: Our data demonstrate large interpatient variability and variable therapy-induced changes independent of the type of therapy. We identify the presence of previously described AXL+ and MITF+ subpopulations in metastatic tissues both at the mRNA level and in situ at the protein level, and demonstrate that MITF+ melanoma cells are significantly decreased upon immunotherapy, while AXL+ melanoma cell numbers are stable. MITF+ tumor cells showed the most significant inverse correlation with CD8+ T cells. Our patient cohort also shows that immunotherapy-induced changes in the abundance of AXL+ or MITF+ tumor cells did not correlate with improved survival. Conclusions: Overall, this study suggests that more differentiated MITF+ tumors are efficiently targeted by immunotherapy, while AXL+ tumor cells may be more resistant, analogous to their response to targeted therapy. |
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| ISSN: | 2590-0188 |