{
  "abstract": "Background Melanoma shows one of the highest response rates to immune checkpoint inhibitors (ICIs), yet nearly half of patients experience primary or acquired resistance. While immune contexture strongly influences therapeutic efficacy, tumor cell-intrinsic features are increasingly recognized as key regulators of antitumor immunity. In particular, intratumoral heterogeneity driven by melanoma cell plasticity underlies diverse immune escape mechanisms. How this plasticity shapes ICI outcomes in patients remains poorly defined.Methods Tumor cell states and immune contexture were assessed in 57 primary cutaneous melanomas from stage III patients, collected prior to adjuvant anti-programmed cell death protein-1 (anti-PD-1) therapy and stratified according to 2-year relapse status (33 relapse-free, 24 relapsed). Whole slide multiplex immunofluorescence was combined with spatial transcriptomics (Visium, n=4) to investigate the spatial architecture of melanoma cell states, T cells, tumor-associated macrophages (TAMs), dendritic cell subsets, and tertiary lymphoid structures.Results Unsupervised clustering of melanoma cells identified distinct phenotypic states that formed spatially restricted homotypic patches. From these data, we defined a melanoma plasticity ratio (undifferentiated/differentiated tumor patches), which was significantly associated with reduced relapse-free survival. Integrated immune analyses recapitulated prognostically distinct immunotypes, with macrophage subsets displaying striking spatial compartmentalization. Antitumoral macrophages preferentially infiltrated differentiated melanoma regions, while protumoral macrophages localized to undifferentiated patches. Spatial transcriptomics confirmed that melanoma cell states tightly shape the neighboring immune microenvironment, with macrophages emerging as pivotal players. Their polarization was further influenced by tumor-derived signals in addition to microenvironmental cues (interferon-gamma, hypoxia). Entropy-based integration of melanoma cell states, TAMs, and T cell subsets uncovered two dominant spatial ecosystems with opposing associations to ICI efficacy. Ecosystems enriched in differentiated melanoma cells, programmed death-ligand 1 (PD-L1) + TAMs, and PD-1+CD8+, and CD4+ T cells correlated with favorable outcomes, whereas ecosystems composed of undifferentiated melanoma cells with PD-L1− protumoral TAMs and PD-1−CD8+ T cells were associated with relapse.Conclusions Our study uncovers how cancer cell plasticity shapes spatially organized tumor-immune ecosystems that critically modulate adjuvant ICI efficacy in melanoma. These findings highlight melanoma cell plasticity as a key driver of immune evasion via macrophages reprogramming, through targetable interactions that may represent novel therapeutic avenues to enhance ICI efficacy.",
  "authors": [
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France",
        "Dermatology Department, Hospices Civils de Lyon, Pierre Bénite, France"
      ],
      "name": "Félix K Pham"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Marion Dufeu"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Valentin Benboubker"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Maxime Grimont"
    },
    {
      "affiliations": [
        "INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon Immunotherapy for Cancer Laboratory (LICL), Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Amélie Lhorisson"
    },
    {
      "affiliations": [
        "INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon Immunotherapy for Cancer Laboratory (LICL), Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Justine Berthet"
    },
    {
      "affiliations": [
        "Pathology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France"
      ],
      "name": "Marie Donzel"
    },
    {
      "affiliations": [
        "Plateforme de bio-informatique Gilles Thomas, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Fondation Synergie Lyon Cancer, Lyon, France"
      ],
      "name": "Raphaël Schneider"
    },
    {
      "affiliations": [
        "Plateforme de bio-informatique Gilles Thomas, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Fondation Synergie Lyon Cancer, Lyon, France"
      ],
      "name": "Laurie Tonon"
    },
    {
      "affiliations": [
        "INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon Immunotherapy for Cancer Laboratory (LICL), Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Anne-Claire Doffin"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Félix Boivin"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Simon Durand"
    },
    {
      "affiliations": [
        "INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon Immunotherapy for Cancer Laboratory (LICL), Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Bertrand Dubois"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France",
        "Hospices Civils de Lyon, Pierre Bénite, France"
      ],
      "name": "Jonathan Lopez"
    },
    {
      "affiliations": [
        "INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon Immunotherapy for Cancer Laboratory (LICL), Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Christophe Caux"
    },
    {
      "affiliations": [
        "INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon Immunotherapy for Cancer Laboratory (LICL), Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Jenny Valladeau-Guilemond"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France",
        "Dermatology Department, Hospices Civils de Lyon, Pierre Bénite, France"
      ],
      "name": "Anaïs Eberhardt"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France",
        "Dermatology Department, Hospices Civils de Lyon, Pierre Bénite, France"
      ],
      "name": "Stéphane Dalle"
    },
    {
      "affiliations": [
        "“Cancer cell Plasticity in Melanoma” lab, “Equipe labellisée Ligue Contre le Cancer”, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Centre de Recherche en Cancérologie de Lyon, Lyon, France"
      ],
      "name": "Julie Caramel"
    }
  ],
  "title": "Melanoma cell states shape spatial tumor-immune ecosystems to dictate the efficacy of anti-PD1 immunotherapy",
  "uid": "ec19c793-3b61-51ee-ab77-4d4785eac292"
}