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Tertiary lymphoid structures improve immunotherapy and survival in melanoma

Cabrita, Rita LU ; Lauss, Martin LU ; Sanna, Adriana LU ; Donia, Marco ; Skaarup Larsen, Mathilde ; Mitra, Shamik LU ; Johansson, Iva LU ; Phung, Bengt LU ; Harbst, Katja LU and Vallon-Christersson, Johan LU , et al. (2020) In Nature 577(7791). p.561-565
Abstract

Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B... (More)

Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
577
issue
7791
pages
5 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:31942071
  • scopus:85078123517
ISSN
0028-0836
DOI
10.1038/s41586-019-1914-8
language
English
LU publication?
yes
id
f30d51a5-8e0b-4aaa-a880-8771599cd262
date added to LUP
2020-02-05 10:04:57
date last changed
2021-05-05 02:34:53
@article{f30d51a5-8e0b-4aaa-a880-8771599cd262,
  abstract     = {<p>Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers<sup>1</sup>. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota<sup>2,3</sup>. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8<sup>+</sup> T cells and CD20<sup>+</sup> B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8<sup>+</sup>CD20<sup>+</sup> tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7<sup>+</sup> naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.</p>},
  author       = {Cabrita, Rita and Lauss, Martin and Sanna, Adriana and Donia, Marco and Skaarup Larsen, Mathilde and Mitra, Shamik and Johansson, Iva and Phung, Bengt and Harbst, Katja and Vallon-Christersson, Johan and van Schoiack, Alison and Lövgren, Kristina and Warren, Sarah and Jirström, Karin and Olsson, Håkan and Pietras, Kristian and Ingvar, Christian and Isaksson, Karolin and Schadendorf, Dirk and Schmidt, Henrik and Bastholt, Lars and Carneiro, Ana and Wargo, Jennifer A. and Svane, Inge Marie and Jönsson, Göran},
  issn         = {0028-0836},
  language     = {eng},
  number       = {7791},
  pages        = {561--565},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Tertiary lymphoid structures improve immunotherapy and survival in melanoma},
  url          = {http://dx.doi.org/10.1038/s41586-019-1914-8},
  doi          = {10.1038/s41586-019-1914-8},
  volume       = {577},
  year         = {2020},
}