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Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors

BACKGROUND: As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prog...

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Autores principales: Yang, Dong, Duan, Mei-Han, Yuan, Qiu-Er, Li, Zhi-Ling, Luo, Chuang-Hua, Cui, Lan-Yue, Li, Li-Chao, Xiao, Ying, Zhu, Xian-Ying, Zhang, Hai-Liang, Feng, Gong-Kan, Liu, Guo-Chen, Deng, Rong, Li, Jun-Dong, Zhu, Xiao-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10472577/
https://www.ncbi.nlm.nih.gov/pubmed/37658364
http://dx.doi.org/10.1186/s12967-023-04422-x
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author Yang, Dong
Duan, Mei-Han
Yuan, Qiu-Er
Li, Zhi-Ling
Luo, Chuang-Hua
Cui, Lan-Yue
Li, Li-Chao
Xiao, Ying
Zhu, Xian-Ying
Zhang, Hai-Liang
Feng, Gong-Kan
Liu, Guo-Chen
Deng, Rong
Li, Jun-Dong
Zhu, Xiao-Feng
author_facet Yang, Dong
Duan, Mei-Han
Yuan, Qiu-Er
Li, Zhi-Ling
Luo, Chuang-Hua
Cui, Lan-Yue
Li, Li-Chao
Xiao, Ying
Zhu, Xian-Ying
Zhang, Hai-Liang
Feng, Gong-Kan
Liu, Guo-Chen
Deng, Rong
Li, Jun-Dong
Zhu, Xiao-Feng
author_sort Yang, Dong
collection PubMed
description BACKGROUND: As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy. METHODS: The 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature. RESULTS: The SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs’ marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer. CONCLUSIONS: The stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04422-x.
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spelling pubmed-104725772023-09-02 Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors Yang, Dong Duan, Mei-Han Yuan, Qiu-Er Li, Zhi-Ling Luo, Chuang-Hua Cui, Lan-Yue Li, Li-Chao Xiao, Ying Zhu, Xian-Ying Zhang, Hai-Liang Feng, Gong-Kan Liu, Guo-Chen Deng, Rong Li, Jun-Dong Zhu, Xiao-Feng J Transl Med Research BACKGROUND: As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy. METHODS: The 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature. RESULTS: The SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs’ marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer. CONCLUSIONS: The stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04422-x. BioMed Central 2023-09-01 /pmc/articles/PMC10472577/ /pubmed/37658364 http://dx.doi.org/10.1186/s12967-023-04422-x Text en © The Author(s) 2023 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Yang, Dong
Duan, Mei-Han
Yuan, Qiu-Er
Li, Zhi-Ling
Luo, Chuang-Hua
Cui, Lan-Yue
Li, Li-Chao
Xiao, Ying
Zhu, Xian-Ying
Zhang, Hai-Liang
Feng, Gong-Kan
Liu, Guo-Chen
Deng, Rong
Li, Jun-Dong
Zhu, Xiao-Feng
Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors
title Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors
title_full Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors
title_fullStr Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors
title_full_unstemmed Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors
title_short Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors
title_sort suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by pdgfrb inhibitors
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10472577/
https://www.ncbi.nlm.nih.gov/pubmed/37658364
http://dx.doi.org/10.1186/s12967-023-04422-x
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