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Molecular patterns of resistance to immune checkpoint blockade in melanoma

Author

Listed:
  • Martin Lauss

    (Lund University
    LUCC)

  • Bengt Phung

    (Lund University
    LUCC)

  • Troels Holz Borch

    (Copenhagen University Hospital)

  • Katja Harbst

    (Lund University
    LUCC)

  • Kamila Kaminska

    (Lund University
    LUCC)

  • Anna Ebbesson

    (Lund University
    LUCC)

  • Ingrid Hedenfalk

    (Lund University
    LUCC)

  • Joan Yuan

    (Lund University)

  • Kari Nielsen

    (LUCC
    Lund University)

  • Christian Ingvar

    (Lund University)

  • Ana Carneiro

    (Lund University
    Skåne University Hospital Comprehensive Cancer Center)

  • Karolin Isaksson

    (LUCC
    Lund University
    Kristianstad Hospital)

  • Kristian Pietras

    (LUCC
    Lund University)

  • Inge Marie Svane

    (Copenhagen University Hospital)

  • Marco Donia

    (Copenhagen University Hospital)

  • Göran Jönsson

    (Lund University
    LUCC)

Abstract

Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect biopsies from a cohort of 44 patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways are observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions have a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and T cell receptor (TCR) clonality analyses. One anti-PD1 resistant lesion harbors a distinct immune cell niche, however, anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. Such immune poor microenvironments are associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors have reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.

Suggested Citation

  • Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47425-y
    DOI: 10.1038/s41467-024-47425-y
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