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Kristian Pietras

Kristian Pietras

Research team manager

Kristian Pietras

Molecular patterns of resistance to immune checkpoint blockade in melanoma

Author

  • 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
  • Kristian Pietras
  • Inge Marie Svane
  • Marco Donia
  • Göran Jönsson
Show all

Summary, in English

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.

Department/s

  • Melanoma Genomics
  • LUCC: Lund University Cancer Centre
  • Lund Melanoma Study Group
  • Melanoma
  • Breast and Ovarian Cancer Genomics
  • Division of Molecular Hematology (DMH)
  • Developmental Immunology
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • LUSCaR- Lund University Skin Cancer Research group
  • Division of Translational Cancer Research
  • Experimental oncology

Publishing year

2024-12

Language

English

Publication/Series

Nature Communications

Volume

15

Issue

1

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cancer and Oncology

Status

Published

Research group

  • Melanoma Genomics
  • Lund Melanoma Study Group
  • Breast and Ovarian Cancer Genomics
  • Developmental Immunology
  • LUSCaR- Lund University Skin Cancer Research group
  • Experimental oncology

ISBN/ISSN/Other

  • ISSN: 2041-1723