Molecular patterns of resistance to immune checkpoint blockade in melanoma
(2024) In Nature Communications 15(1).- 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... (More)
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.
(Less)
- author
- organization
-
- Melanoma Genomics (research group)
- LUCC: Lund University Cancer Centre
- Lund Melanoma Study Group (research group)
- Melanoma
- Breast and Ovarian Cancer Genomics (research group)
- Division of Molecular Hematology (DMH)
- Developmental Immunology (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- LUSCaR- Lund University Skin Cancer Research group (research group)
- Division of Translational Cancer Research
- Experimental oncology (research group)
- publishing date
- 2024-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 15
- issue
- 1
- article number
- 3075
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:38594286
- scopus:85189952926
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-024-47425-y
- language
- English
- LU publication?
- yes
- id
- c5c83070-3537-4c6c-a42d-acce0736ac83
- date added to LUP
- 2024-04-19 15:10:43
- date last changed
- 2024-06-14 20:26:42
@article{c5c83070-3537-4c6c-a42d-acce0736ac83, abstract = {{<p>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<sup>+</sup> CD8<sup>+</sup> 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.</p>}}, author = {{Lauss, Martin and Phung, Bengt and Borch, Troels Holz and Harbst, Katja and Kaminska, Kamila and Ebbesson, Anna and Hedenfalk, Ingrid and Yuan, Joan and Nielsen, Kari and Ingvar, Christian and Carneiro, Ana and Isaksson, Karolin and Pietras, Kristian and Svane, Inge Marie and Donia, Marco and Jönsson, Göran}}, issn = {{2041-1723}}, language = {{eng}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Molecular patterns of resistance to immune checkpoint blockade in melanoma}}, url = {{http://dx.doi.org/10.1038/s41467-024-47425-y}}, doi = {{10.1038/s41467-024-47425-y}}, volume = {{15}}, year = {{2024}}, }