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CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer

BACKGROUND: Response to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. How...

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Autores principales: Seitz, Stefanie, Dreyer, Tobias F., Stange, Christoph, Steiger, Katja, Bräuer, Rosalinde, Scheutz, Leandra, Multhoff, Gabriele, Weichert, Wilko, Kiechle, Marion, Magdolen, Viktor, Bronger, Holger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090786/
https://www.ncbi.nlm.nih.gov/pubmed/35314795
http://dx.doi.org/10.1038/s41416-022-01763-0
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author Seitz, Stefanie
Dreyer, Tobias F.
Stange, Christoph
Steiger, Katja
Bräuer, Rosalinde
Scheutz, Leandra
Multhoff, Gabriele
Weichert, Wilko
Kiechle, Marion
Magdolen, Viktor
Bronger, Holger
author_facet Seitz, Stefanie
Dreyer, Tobias F.
Stange, Christoph
Steiger, Katja
Bräuer, Rosalinde
Scheutz, Leandra
Multhoff, Gabriele
Weichert, Wilko
Kiechle, Marion
Magdolen, Viktor
Bronger, Holger
author_sort Seitz, Stefanie
collection PubMed
description BACKGROUND: Response to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. However, the function of CXCL9 in ovarian cancer has been poorly studied. METHODS: Impact of Cxcl9 overexpression in the murine ID8-Trp53(−/−) and ID8-Trp53(−/–)Brca2(−/−) ovarian cancer models on survival, cellular immune composition, PD-L1 expression and anti-PD-L1 therapy. CXCL9 expression analysis in ovarian cancer subtypes and correlation to reported ICB response. RESULTS: CXCL9 overexpression resulted in T-cell accumulation, delayed ascites formation and improved survival, which was dependent on adaptive immune function. In the ICB-resistant mouse model, the chemokine was sufficient to enable a successful anti-PD-L1 therapy. In contrast, these effects were abrogated in Brca2-deficient tumours, most likely due to an already high intrinsic chemokine expression. Finally, in ovarian cancer patients, the clear-cell subtype, known to respond best to ICB, displayed a significantly higher proportion of CXCL9(high) tumours than the other subtypes. CONCLUSIONS: CXCL9 is a driver of successful ICB in preclinical ovarian cancer. Besides being a feasible predictive biomarker, CXCL9-inducing agents thus represent attractive combination partners to improve ICB in this cancer entity.
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spelling pubmed-90907862022-05-12 CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer Seitz, Stefanie Dreyer, Tobias F. Stange, Christoph Steiger, Katja Bräuer, Rosalinde Scheutz, Leandra Multhoff, Gabriele Weichert, Wilko Kiechle, Marion Magdolen, Viktor Bronger, Holger Br J Cancer Article BACKGROUND: Response to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. However, the function of CXCL9 in ovarian cancer has been poorly studied. METHODS: Impact of Cxcl9 overexpression in the murine ID8-Trp53(−/−) and ID8-Trp53(−/–)Brca2(−/−) ovarian cancer models on survival, cellular immune composition, PD-L1 expression and anti-PD-L1 therapy. CXCL9 expression analysis in ovarian cancer subtypes and correlation to reported ICB response. RESULTS: CXCL9 overexpression resulted in T-cell accumulation, delayed ascites formation and improved survival, which was dependent on adaptive immune function. In the ICB-resistant mouse model, the chemokine was sufficient to enable a successful anti-PD-L1 therapy. In contrast, these effects were abrogated in Brca2-deficient tumours, most likely due to an already high intrinsic chemokine expression. Finally, in ovarian cancer patients, the clear-cell subtype, known to respond best to ICB, displayed a significantly higher proportion of CXCL9(high) tumours than the other subtypes. CONCLUSIONS: CXCL9 is a driver of successful ICB in preclinical ovarian cancer. Besides being a feasible predictive biomarker, CXCL9-inducing agents thus represent attractive combination partners to improve ICB in this cancer entity. Nature Publishing Group UK 2022-03-21 2022-06-01 /pmc/articles/PMC9090786/ /pubmed/35314795 http://dx.doi.org/10.1038/s41416-022-01763-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Seitz, Stefanie
Dreyer, Tobias F.
Stange, Christoph
Steiger, Katja
Bräuer, Rosalinde
Scheutz, Leandra
Multhoff, Gabriele
Weichert, Wilko
Kiechle, Marion
Magdolen, Viktor
Bronger, Holger
CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer
title CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer
title_full CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer
title_fullStr CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer
title_full_unstemmed CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer
title_short CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer
title_sort cxcl9 inhibits tumour growth and drives anti-pd-l1 therapy in ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090786/
https://www.ncbi.nlm.nih.gov/pubmed/35314795
http://dx.doi.org/10.1038/s41416-022-01763-0
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