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Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer
Inflammation is a common medical complication in colorectal cancer (CRC) patients, which plays significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICI) is incompletely understood. Here...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9705377/ https://www.ncbi.nlm.nih.gov/pubmed/36443332 http://dx.doi.org/10.1038/s41467-022-35096-6 |
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author | Sui, Qiaoqi Zhang, Xi Chen, Chao Tang, Jinghua Yu, Jiehai Li, Weihao Han, Kai Jiang, Wu Liao, Leen Kong, Lingheng Li, Yuan Hou, Zhenlin Zhou, Chi Zhang, Chenzhi Zhang, Linjie Xiao, Binyi Mei, Weijian Xu, Yanbo Qin, Jiayi Zheng, Jian Pan, Zhizhong Ding, Pei-Rong |
author_facet | Sui, Qiaoqi Zhang, Xi Chen, Chao Tang, Jinghua Yu, Jiehai Li, Weihao Han, Kai Jiang, Wu Liao, Leen Kong, Lingheng Li, Yuan Hou, Zhenlin Zhou, Chi Zhang, Chenzhi Zhang, Linjie Xiao, Binyi Mei, Weijian Xu, Yanbo Qin, Jiayi Zheng, Jian Pan, Zhizhong Ding, Pei-Rong |
author_sort | Sui, Qiaoqi |
collection | PubMed |
description | Inflammation is a common medical complication in colorectal cancer (CRC) patients, which plays significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICI) is incompletely understood. Here we show that in a patient with high microsatellite instability (MSI-H) CRC and a local inflammatory condition, the primary tumor progresses but its liver metastasis regresses upon Pembrolizumab treatment. In silico investigation prompted by this observation confirms correlation between inflammatory conditions and poor tumor response to PD-1 blockade in MSI-H CRCs, which is further validated in a cohort of 62 patients retrospectively enrolled to our study. Inhibition of local but not systemic immune response is verified in cultures of paired T cells and organoid cells from patients. Single-cell RNA sequencing suggests involvement of neutrophil leukocytes via CD80/CD86-CTLA4 signaling in the suppressive immune microenvironment. In concordance with this finding, elevated neutrophil-to-lymphocyte ratio indicates inhibited immune status and poor tumor response to ICIs. Receiver operating characteristic curve further demonstrates that both inflammatory conditions and a high NLR could predict a poor response to ICIs in MSI- CRCs, and the predictive value could be further increased when these two predictors are combined. Our study thus suggests that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil leukocyte associated immunosuppression and proposes both inflammatory conditions and high neutrophil-to-lymphocyte ratio as clinical features for poor ICI response. |
format | Online Article Text |
id | pubmed-9705377 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-97053772022-11-30 Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer Sui, Qiaoqi Zhang, Xi Chen, Chao Tang, Jinghua Yu, Jiehai Li, Weihao Han, Kai Jiang, Wu Liao, Leen Kong, Lingheng Li, Yuan Hou, Zhenlin Zhou, Chi Zhang, Chenzhi Zhang, Linjie Xiao, Binyi Mei, Weijian Xu, Yanbo Qin, Jiayi Zheng, Jian Pan, Zhizhong Ding, Pei-Rong Nat Commun Article Inflammation is a common medical complication in colorectal cancer (CRC) patients, which plays significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICI) is incompletely understood. Here we show that in a patient with high microsatellite instability (MSI-H) CRC and a local inflammatory condition, the primary tumor progresses but its liver metastasis regresses upon Pembrolizumab treatment. In silico investigation prompted by this observation confirms correlation between inflammatory conditions and poor tumor response to PD-1 blockade in MSI-H CRCs, which is further validated in a cohort of 62 patients retrospectively enrolled to our study. Inhibition of local but not systemic immune response is verified in cultures of paired T cells and organoid cells from patients. Single-cell RNA sequencing suggests involvement of neutrophil leukocytes via CD80/CD86-CTLA4 signaling in the suppressive immune microenvironment. In concordance with this finding, elevated neutrophil-to-lymphocyte ratio indicates inhibited immune status and poor tumor response to ICIs. Receiver operating characteristic curve further demonstrates that both inflammatory conditions and a high NLR could predict a poor response to ICIs in MSI- CRCs, and the predictive value could be further increased when these two predictors are combined. Our study thus suggests that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil leukocyte associated immunosuppression and proposes both inflammatory conditions and high neutrophil-to-lymphocyte ratio as clinical features for poor ICI response. Nature Publishing Group UK 2022-11-28 /pmc/articles/PMC9705377/ /pubmed/36443332 http://dx.doi.org/10.1038/s41467-022-35096-6 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 Sui, Qiaoqi Zhang, Xi Chen, Chao Tang, Jinghua Yu, Jiehai Li, Weihao Han, Kai Jiang, Wu Liao, Leen Kong, Lingheng Li, Yuan Hou, Zhenlin Zhou, Chi Zhang, Chenzhi Zhang, Linjie Xiao, Binyi Mei, Weijian Xu, Yanbo Qin, Jiayi Zheng, Jian Pan, Zhizhong Ding, Pei-Rong Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer |
title | Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer |
title_full | Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer |
title_fullStr | Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer |
title_full_unstemmed | Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer |
title_short | Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer |
title_sort | inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9705377/ https://www.ncbi.nlm.nih.gov/pubmed/36443332 http://dx.doi.org/10.1038/s41467-022-35096-6 |
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