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Tumor-resident T cells and dendritic cells form an in situ archetype for immunotherapy response in melanoma [bulk RNA-seq]

ABSTRACT: Tumor-resident (TR) T cells participate in immunosurveillance of melanoma, but their role in determining response to immune checkpoint inhibitors (ICI) has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant, or ICI-responsive patients. In responders, we found enrichment for early differentiation (TCF1+) CD8+ and CD4+ TR which co-localized with melanoma cells. CD8+ TR were hyperexpanded, and both CD8+ and CD4+ TR upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ responses within the tumor microenvironment to potentiate T cell exhaustion. In ICI-responsive melanoma tumors, CD8⁺ TR interact with CD4⁺ TR cells (via the CCL4-CCR5 axis) and engage with type-3 dendritic cells (DC3) (via IL15-IL15R interaction). This intratumoral immune triad (CD8⁺ TR – CD4⁺ TR – DC) is exclusive to responders. This study illustrates the role of TR cells and their crosstalk with DCs in effective ICI responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294272 | GEO | 2026/06/08

REPOSITORIES: GEO

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Project description:Background Immune checkpoint inhibitor (ICI) has greatly improved the prognosis of advanced melanoma. Whereas the efficacy in Japanese patients has been found to be lower than Caucasian, the genomic and transcriptomic features associated with response to ICI of Japanese melanomas remain to be elucidated. Patients and methods Total 129 tumour samples from 78 melanoma patients, who received therapeutic regimens with or without ICI treatment, were collected at 13 institutions in Japan. We performed exome and RNA sequencing and investigated the association of genomic and transcriptomic factors with clinical efficacy of ICI therapy. Time-course data were also analysed. This is the first and largest genomic cohort study for Japanese melanoma, in which tumour samples were prospectively analysed. Results Number of somatic SNVs of Japanese melanomas is lower than that of TCGA Caucasian data due to the biased distribution of WHO subtypes. Driver subtypes of BRAF, NRAS and NF1 was less prevalent but Triple Wildtype predominantly existed in the Japanese cohort. Whereas exome-wide survey revealed no significant association of mutated genes with ICI response, by transcriptomic analysis we identified inflammation-associated genes including several chemokines and cytokines were highly expressed in responders. Follicular helper T cells estimated by immune-cell composition analysis were found significantly enriched in responders (p = 0.0422). Through time-course transcriptome analysis, in addition to several cytotoxic T-cell genes as previously reported, MARCO on tumour-associated macrophages was found induced by ICI treatment in responders (p = 0.0040). The protein expression of these genes was confirmed by immunohistochemical and multiplex immunofluorescent analyses. Some of these genes can be useful biomarkers for prediction of ICI response in the treatment of Japanese melanoma. Conclusions Through prospective genomic and transcriptomic analyses of Japanese melanoma samples, candidate biomarkers for ICI treatment were identified.

Project description:Background:Acral melanoma (AM) has distinct characteristics as compared to cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICI). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. Methods: We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. Results: 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3 + CD8 + PD1 + intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low vs high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared to responders across cancers, including acral melanoma, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. Conclusions: A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.

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Tumor-resident T cells and dendritic cells form an in situ archetype for immunotherapy response in melanoma [bulk RNA-seq]

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