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High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition
Various immune signatures predictive of resistance to immune checkpoint inhibitors (ICI) have been described in multiple solid cancers, but still under-investigated in gynecological (GYN) cancer. For 49 GYN cancer patients included in our study, without transcriptome signature, immune-related toxici...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683510/ https://www.ncbi.nlm.nih.gov/pubmed/34921236 http://dx.doi.org/10.1038/s41698-021-00242-8 |
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author | Ni, Ying Soliman, Ahmed Joehlin-Price, Amy Rose, Peter G. Vlad, Anda Edwards, Robert P. Mahdi, Haider |
author_facet | Ni, Ying Soliman, Ahmed Joehlin-Price, Amy Rose, Peter G. Vlad, Anda Edwards, Robert P. Mahdi, Haider |
author_sort | Ni, Ying |
collection | PubMed |
description | Various immune signatures predictive of resistance to immune checkpoint inhibitors (ICI) have been described in multiple solid cancers, but still under-investigated in gynecological (GYN) cancer. For 49 GYN cancer patients included in our study, without transcriptome signature, immune-related toxicity was the only clinical predictor of ICI treatment response (p = 0.008). The objective clinical response was the only predictor of progression-free survival (ICI-PFS, p = 0.0008) and overall survival (ICI-OS, p = 0.01). Commonly used ICI marker PD-L1 expression negatively correlated with progression-free survival (ICI-PFS) (p = 0.0019). We performed transcriptome and signaling pathway enrichment analyses based on ICI treatment responses and the survival outcome, and further estimated immune cell abundance using 547 gene markers. Our data revealed that TGF-β regulated signaling pathway was noted to play an important role in immunotherapy failure. Using our 6-genes TGF-β score, we observed longer ICI-PFS associated with lower TGF-β score (8.1 vs. 2.8 months, p = 0.046), which was especially more prominent in ovarian cancer (ICI-PFS 16.6 vs. 2.65 months, p = 0.0012). Further, abundant immunosuppressive cells like T-regulatory cells, eosinophils, and M2 macrophages were associated with shorter ICI-OS and correlated positively with CD274 and CTLA4 expressions. This study provides insight on the potential role of TGF-β in mediating immunotherapy resistance and cross-talking to immunosuppressive environment in GYN cancer. The TGF-β score, if validated in a larger cohort, can identify patients who likely to fail ICI and benefit from targeting this pathway to enhance the response to ICI. |
format | Online Article Text |
id | pubmed-8683510 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86835102022-01-04 High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition Ni, Ying Soliman, Ahmed Joehlin-Price, Amy Rose, Peter G. Vlad, Anda Edwards, Robert P. Mahdi, Haider NPJ Precis Oncol Article Various immune signatures predictive of resistance to immune checkpoint inhibitors (ICI) have been described in multiple solid cancers, but still under-investigated in gynecological (GYN) cancer. For 49 GYN cancer patients included in our study, without transcriptome signature, immune-related toxicity was the only clinical predictor of ICI treatment response (p = 0.008). The objective clinical response was the only predictor of progression-free survival (ICI-PFS, p = 0.0008) and overall survival (ICI-OS, p = 0.01). Commonly used ICI marker PD-L1 expression negatively correlated with progression-free survival (ICI-PFS) (p = 0.0019). We performed transcriptome and signaling pathway enrichment analyses based on ICI treatment responses and the survival outcome, and further estimated immune cell abundance using 547 gene markers. Our data revealed that TGF-β regulated signaling pathway was noted to play an important role in immunotherapy failure. Using our 6-genes TGF-β score, we observed longer ICI-PFS associated with lower TGF-β score (8.1 vs. 2.8 months, p = 0.046), which was especially more prominent in ovarian cancer (ICI-PFS 16.6 vs. 2.65 months, p = 0.0012). Further, abundant immunosuppressive cells like T-regulatory cells, eosinophils, and M2 macrophages were associated with shorter ICI-OS and correlated positively with CD274 and CTLA4 expressions. This study provides insight on the potential role of TGF-β in mediating immunotherapy resistance and cross-talking to immunosuppressive environment in GYN cancer. The TGF-β score, if validated in a larger cohort, can identify patients who likely to fail ICI and benefit from targeting this pathway to enhance the response to ICI. Nature Publishing Group UK 2021-12-17 /pmc/articles/PMC8683510/ /pubmed/34921236 http://dx.doi.org/10.1038/s41698-021-00242-8 Text en © The Author(s) 2021 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 Ni, Ying Soliman, Ahmed Joehlin-Price, Amy Rose, Peter G. Vlad, Anda Edwards, Robert P. Mahdi, Haider High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition |
title | High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition |
title_full | High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition |
title_fullStr | High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition |
title_full_unstemmed | High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition |
title_short | High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition |
title_sort | high tgf-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683510/ https://www.ncbi.nlm.nih.gov/pubmed/34921236 http://dx.doi.org/10.1038/s41698-021-00242-8 |
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