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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Elsevier
2024-12-01
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| Series: | Immuno-Oncology and Technology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S259001882400306X |
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| author | M. Willemsen J. Bulgarelli S.K. Chauhan R.R. Lereim D. Angeli G. Grisendi G. Krebbers I. Davidson J.A. Kyte M. Guidoboni R.M. Luiten W.J. Bakker |
| author_facet | M. Willemsen J. Bulgarelli S.K. Chauhan R.R. Lereim D. Angeli G. Grisendi G. Krebbers I. Davidson J.A. Kyte M. Guidoboni R.M. Luiten W.J. Bakker |
| author_sort | M. Willemsen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-682d4469f2004d579e9cf259ac2e73d1 |
| institution | OA Journals |
| issn | 2590-0188 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Immuno-Oncology and Technology |
| spelling | doaj-art-682d4469f2004d579e9cf259ac2e73d12025-08-20T01:58:16ZengElsevierImmuno-Oncology and Technology2590-01882024-12-012410100910.1016/j.iotech.2024.101009Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapyM. Willemsen0J. Bulgarelli1S.K. Chauhan2R.R. Lereim3D. Angeli4G. Grisendi5G. Krebbers6I. Davidson7J.A. Kyte8M. Guidoboni9R.M. Luiten10W.J. Bakker11Department 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 NetherlandsImmunotherapy Cell Therapy and Biobank (ITCB) Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyDepartment of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, NorwayDepartment of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, NorwayUnit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyLaboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, ItalyDepartment 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 NetherlandsDepartment of Functional Genomics and Cancer, IGBMC, CNRS/INSERM, Illkirch, FranceDepartment of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Clinical Cancer Research, Oslo University Hospital, Oslo, NorwayDepartment of Oncology, Ferrara University Hospital, University of Ferrara, Ferrara, Italy; Correspondence to: Prof. Massimo Guidoboni, Department of Oncology, Ferrara University Hospital, University of Ferrara, via Aldo Moro 8, 44124 Ferrara, Italy. Tel: +390532237124Department 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; Prof. Rosalie M. Luiten, Department of Dermatology, Amsterdam UMC, location AMC, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Tel: +31205665304Department 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 NetherlandsBackground: 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.http://www.sciencedirect.com/science/article/pii/S259001882400306XmelanomaAXLMITFDC vaccinationimmune checkpointtumor heterogeneity |
| spellingShingle | M. Willemsen J. Bulgarelli S.K. Chauhan R.R. Lereim D. Angeli G. Grisendi G. Krebbers I. Davidson J.A. Kyte M. Guidoboni R.M. Luiten W.J. Bakker Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy Immuno-Oncology and Technology melanoma AXL MITF DC vaccination immune checkpoint tumor heterogeneity |
| title | Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy |
| title_full | Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy |
| title_fullStr | Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy |
| title_full_unstemmed | Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy |
| title_short | Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy |
| title_sort | changes in axl and or mitf melanoma subpopulations in patients receiving immunotherapy |
| topic | melanoma AXL MITF DC vaccination immune checkpoint tumor heterogeneity |
| url | http://www.sciencedirect.com/science/article/pii/S259001882400306X |
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