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Updated: Jun 4, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy
M Willemsen1, J Bulgarelli2, S K Chauhan3
1Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands.
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.
Insights
Tumor heterogeneity impacts immunotherapy response. This study found that while MITF+ melanoma cells decrease with immunotherapy, AXL+ cells remain stable, suggesting AXL+ cells may be resistant to treatment.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Tumor heterogeneity poses challenges for effective cancer therapies, particularly immunotherapy.
- AXL+ tumor cells exhibit resistance to targeted therapy, while MITF+ tumor cells respond to RAF and MEK inhibitors.
Purpose of the Study:
- To analyze tumor heterogeneity in metastatic tissues.
- To investigate the presence and behavior of AXL+ and MITF+ melanoma subpopulations.
- To correlate these subpopulations with immune pressure and response to immunotherapy.
Main Methods:
- NanoString gene expression analysis
- Single-cell RNA sequencing
- In situ multiplex immunofluorescence
- Analysis of immunotherapy response (immunomodulating antibodies, dendritic cell vaccination)
Main Results:
- Significant interpatient variability in therapy-induced changes was observed.
- AXL+ and MITF+ subpopulations were identified at mRNA and protein levels in metastatic tissues.
- MITF+ melanoma cells decreased with immunotherapy, while AXL+ cells remained stable.
- MITF+ cells showed an inverse correlation with CD8+ T cells.
- Changes in AXL+ or MITF+ cell abundance did not correlate with improved survival.
Conclusions:
- MITF+ melanoma cells are effectively targeted by immunotherapy.
- AXL+ tumor cells may exhibit resistance to immunotherapy, similar to their resistance to targeted therapy.
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