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Molecular patterns of resistance to immune checkpoint blockade in melanoma

Lauss, Martin LU ; Phung, Bengt LU ; Borch, Troels Holz ; Harbst, Katja LU orcid ; Kaminska, Kamila LU ; Ebbesson, Anna LU ; Hedenfalk, Ingrid LU orcid ; Yuan, Joan LU orcid ; Nielsen, Kari LU orcid and Ingvar, Christian LU , et al. (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.

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publishing date
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}},
}