Molecular patterns of resistance to immune checkpoint blockade in melanoma

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 and Göran Jönsson ()
Additional contact information
Martin Lauss: Lund University
Bengt Phung: Lund University
Troels Holz Borch: Copenhagen University Hospital
Katja Harbst: Lund University
Kamila Kaminska: Lund University
Anna Ebbesson: Lund University
Ingrid Hedenfalk: Lund University
Joan Yuan: Lund University
Kari Nielsen: LUCC
Christian Ingvar: Lund University
Ana Carneiro: Lund University
Karolin Isaksson: LUCC
Kristian Pietras: LUCC
Inge Marie Svane: Copenhagen University Hospital
Marco Donia: Copenhagen University Hospital
Göran Jönsson: Lund University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47425-y

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