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<p>Tumor-infiltrating lymphocytes (TILs) shape melanoma behavior and response to immunotherapy, but the links between immune regulation, TIL patterning, and outcomes remain unclear. We retrospectively studied 32 primary melanoma samples from patients treated with anti–PD-1 therapy. Histopathologic TILs were classified as brisk or non-brisk, and primary tumors underwent targeted immune transcriptomic profiling (NanoString nCounter Human Immunology panel). External validation was performed with 96 TCGA-SKCM primary tumors. Brisk tumors displayed broad upregulation of immune transcripts, with enrichment of adhesion pathways (directed global significance scores – DGSS = 2.15) and MHC class II antigen presentation (DGSS = 2.128). Cross-cohort comparison identified 22 shared differentially expressed genes, with <i>ZAP70</i> remaining significant in both datasets. Brisk tumors also showed higher total TIL (<i>p</i> = 0.036), cytotoxic-cell (<i>p</i> = 0.0095), and Th1 (<i>p</i> = 0.027) scores. Response-associated genes differed by TIL pattern, and subgroup-specific gene scores predicted anti–PD-1 benefit in brisk (4-gene, Area under curve - AUC = 1.000) and non-brisk (3-gene, AUC = 0.852) tumors; the non-brisk score remained independently associated with response (<i>p</i> = 0.029). Higher scores were also associated with prolonged survival. Integrating histopathological TIL patterning with immune transcriptomics may refine prognostication and support immunotherapy stratification in melanoma.</p>

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The tumoural landscape of lymphocytes and immune pathways in immunotherapy-treated melanoma patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月15日

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  • Vinícius Gonçalves de Souza,
  • Bruna Pereira Sorroche,
  • Renan de Jesus Teixeira,
  • Hendrigo Nunes,
  • Ana Carolina Laus,
  • Vinícius de Lima Vazquez,
  • Daniele Moraes Losada,
  • Lidia Maria Rebolho Batista Arantes

摘要

Tumor-infiltrating lymphocytes (TILs) shape melanoma behavior and response to immunotherapy, but the links between immune regulation, TIL patterning, and outcomes remain unclear. We retrospectively studied 32 primary melanoma samples from patients treated with anti–PD-1 therapy. Histopathologic TILs were classified as brisk or non-brisk, and primary tumors underwent targeted immune transcriptomic profiling (NanoString nCounter Human Immunology panel). External validation was performed with 96 TCGA-SKCM primary tumors. Brisk tumors displayed broad upregulation of immune transcripts, with enrichment of adhesion pathways (directed global significance scores – DGSS = 2.15) and MHC class II antigen presentation (DGSS = 2.128). Cross-cohort comparison identified 22 shared differentially expressed genes, with ZAP70 remaining significant in both datasets. Brisk tumors also showed higher total TIL (p = 0.036), cytotoxic-cell (p = 0.0095), and Th1 (p = 0.027) scores. Response-associated genes differed by TIL pattern, and subgroup-specific gene scores predicted anti–PD-1 benefit in brisk (4-gene, Area under curve - AUC = 1.000) and non-brisk (3-gene, AUC = 0.852) tumors; the non-brisk score remained independently associated with response (p = 0.029). Higher scores were also associated with prolonged survival. Integrating histopathological TIL patterning with immune transcriptomics may refine prognostication and support immunotherapy stratification in melanoma.