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Updated: Oct 10, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Different Response to Immunotherapy According to Melanoma Histologic Subtype
Laura Pala1, Fabio Conforti1, Eleonora Pagan2
1Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors.
Abstract:
Superficial spreading melanoma (SSM) and nodular melanoma (NM) are the most common melanoma histologic subtypes and are characterized by different biological features. We retrospectively analyzed all consecutive patients with advanced melanoma, treated with anti-PD-1 and/or anti-CTLA-4 at our center, with data available on primary tumor subtype. The primary objective was to assess the association between histologic subtype and patients' outcomes. In addition, we analyzed whole-exome and whole-transcriptome sequencing data of a cohort of advanced melanoma to identify genes and related pathways, characterized by significant differences between NMs and SSMs. Twenty-one patients with NM and 39 with SSM, treated with anti-PD-1(53/60) as monotherapy or combined with anti-CTLA-4 (7/60), were analyzed. All known clinical-pathologic prognostic factors were well balanced between NM and SSM groups, except for the ECOG-PS score. The overall response rate was 52.4% (95% confidence interval, 29.8-74.3) in the NMs group versus 20.5% (9.3-36.5) in the SSMs group (P-value=0.02). The median progression-free survival and overall survival were, respectively, 13.9 and 44.5 months in the NMs group versus only 3.2 and 12 months in SSMs group (progression-free survival P-value=0.032; overall survival P-value=0.002). Multivariable analysis adjusting for the ECOG-PS, confirmed similar results. Whole-exome and whole-transcriptome data of 28 NMs and 21 SSMs were analyzed. No significant differences were observed in terms of both TMB and frequency of mutation in any gene. A total of 266 genes were overexpressed in NMs as compared with SSMs, and enrichment-analysis revealed a significant enrichment (false discovery rate<0.05) of genes belonging to immune-related pathways involved in antigens presentation mechanisms, response to interferon gamma and neutrophil activation. We provided clinical evidences suggesting a relevant association between melanoma histologic subtype and response to immunotherapy.
Insights
Melanoma histologic subtypes, nodular melanoma (NM) and superficial spreading melanoma (SSM), show different responses to immunotherapy. NM patients experienced significantly better outcomes and survival rates compared to SSM patients in this study.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Superficial spreading melanoma (SSM) and nodular melanoma (NM) are the most common melanoma subtypes with distinct biological characteristics.
- Understanding subtype-specific responses to cancer immunotherapy is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the association between melanoma histologic subtype (NM vs. SSM) and patient outcomes following treatment with immune checkpoint inhibitors (anti-PD-1 and/or anti-CTLA-4).
- To identify molecular differences, including gene expression and pathway enrichment, between NM and SSM in advanced melanoma patients.
Main Methods:
- Retrospective analysis of advanced melanoma patients treated with anti-PD-1 and/or anti-CTLA-4, categorizing outcomes by primary tumor subtype (NM vs. SSM).
- Whole-exome and whole-transcriptome sequencing were performed on a subset of NM and SSM tumors to compare genetic and transcriptomic profiles.
- Statistical analyses included response rates, progression-free survival, overall survival, and multivariable analysis adjusting for prognostic factors.
Main Results:
- Nodular melanoma (NM) patients exhibited significantly higher overall response rates (52.4% vs. 20.5%, P=0.02) compared to superficial spreading melanoma (SSM) patients.
- Median progression-free survival (13.9 vs. 3.2 months, P=0.032) and overall survival (44.5 vs. 12 months, P=0.002) were substantially longer for NM patients.
- Transcriptomic analysis revealed overexpression of 266 genes in NM, enriched in immune-related pathways such as antigen presentation and interferon gamma response, with no significant differences in tumor mutational burden.
Conclusions:
- Melanoma histologic subtype is a significant factor influencing patient response and survival outcomes in immunotherapy.
- Nodular melanoma appears to be more responsive to immune checkpoint inhibitor therapy than superficial spreading melanoma.
- Distinct molecular pathways, particularly those related to immune response, characterize NM and may contribute to its differential response to immunotherapy.
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