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CD8(+) T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types

BACKGROUND: Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are critical for immune suppression by restricting immune cell infiltration in the tumor stromal zones from penetrating tumor islands and changing their function status, particularly for CD8(+) T cells. However,...

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Autores principales: Zheng, Xinlong, Jiang, Kan, Xiao, Weijin, Zeng, Dongqiang, Peng, Wenying, Bai, Jing, Chen, Xiaohui, Li, Pansong, Zhang, Longfeng, Zheng, Xiaobin, Miao, Qian, Wang, Haibo, Wu, Shiwen, Xu, Yiquan, Xu, Haipeng, Li, Chao, Li, Lifeng, Gao, Xuan, Zheng, Suya, Li, Junhui, Wang, Deqiang, Zhou, Zhipeng, Xia, Xuefeng, Yang, Shanshan, Li, Yujing, Cui, Zhaolei, Zhang, Qiuyu, Chen, Ling, Lin, Xiandong, Lin, Gen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9682254/
https://www.ncbi.nlm.nih.gov/pubmed/36439099
http://dx.doi.org/10.3389/fimmu.2022.974265
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author Zheng, Xinlong
Jiang, Kan
Xiao, Weijin
Zeng, Dongqiang
Peng, Wenying
Bai, Jing
Chen, Xiaohui
Li, Pansong
Zhang, Longfeng
Zheng, Xiaobin
Miao, Qian
Wang, Haibo
Wu, Shiwen
Xu, Yiquan
Xu, Haipeng
Li, Chao
Li, Lifeng
Gao, Xuan
Zheng, Suya
Li, Junhui
Wang, Deqiang
Zhou, Zhipeng
Xia, Xuefeng
Yang, Shanshan
Li, Yujing
Cui, Zhaolei
Zhang, Qiuyu
Chen, Ling
Lin, Xiandong
Lin, Gen
author_facet Zheng, Xinlong
Jiang, Kan
Xiao, Weijin
Zeng, Dongqiang
Peng, Wenying
Bai, Jing
Chen, Xiaohui
Li, Pansong
Zhang, Longfeng
Zheng, Xiaobin
Miao, Qian
Wang, Haibo
Wu, Shiwen
Xu, Yiquan
Xu, Haipeng
Li, Chao
Li, Lifeng
Gao, Xuan
Zheng, Suya
Li, Junhui
Wang, Deqiang
Zhou, Zhipeng
Xia, Xuefeng
Yang, Shanshan
Li, Yujing
Cui, Zhaolei
Zhang, Qiuyu
Chen, Ling
Lin, Xiandong
Lin, Gen
author_sort Zheng, Xinlong
collection PubMed
description BACKGROUND: Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are critical for immune suppression by restricting immune cell infiltration in the tumor stromal zones from penetrating tumor islands and changing their function status, particularly for CD8(+) T cells. However, assessing and quantifying the impact of CAFs on immune cells and investigating how this impact is related to clinical outcomes, especially the efficacy of immunotherapy, remain unclear. MATERIALS AND METHODS: The TME was characterized using immunohistochemical (IHC) analysis using a large-scale sample size of gene expression profiles. The CD8(+) T cell/CAF ratio (CFR) association with survival was investigated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) lung cancer cohorts. The correlation between CFR and immunotherapeutic efficacy was computed in five independent cohorts. The correlation between CFR and objective response rates (ORRs) following pembrolizumab monotherapy was investigated in 20 solid tumor types. To facilitate clinical translation, the IHC-detected CD8/α-SMA ratio was applied as an immunotherapeutic predictive biomarker in a real-world lung cancer cohort. RESULTS: Compared with normal tissue, CAFs were enriched in cancer tissue, and the amount of CAFs was overwhelmingly higher than that in other immune cells. CAFs are positively correlated with the extent of immune infiltration. A higher CFR was strongly associated with improved survival in lung cancer, melanoma, and urothelial cancer immunotherapy cohorts. Within most cohorts, there was no clear evidence for an association between CFR and programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB). Compared with TMB and PD-L1, a higher correlation coefficient was observed between CFR and the ORR following pembrolizumab monotherapy in 20 solid tumor types (Spearman’s r = 0.69 vs. 0.44 and 0.21). In a real-world cohort, patients with a high CFR detected by IHC benefited considerably from immunotherapy as compared with those with a low CFR (hazard ratio, 0.37; 95% confidence interval, 0.19–0.75; p < 0.001). CONCLUSIONS: CFR is a newly found and simple parameter that can be used for identifying patients unlikely to benefit from immunotherapy. Future studies are needed to confirm this finding.
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spelling pubmed-96822542022-11-24 CD8(+) T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types Zheng, Xinlong Jiang, Kan Xiao, Weijin Zeng, Dongqiang Peng, Wenying Bai, Jing Chen, Xiaohui Li, Pansong Zhang, Longfeng Zheng, Xiaobin Miao, Qian Wang, Haibo Wu, Shiwen Xu, Yiquan Xu, Haipeng Li, Chao Li, Lifeng Gao, Xuan Zheng, Suya Li, Junhui Wang, Deqiang Zhou, Zhipeng Xia, Xuefeng Yang, Shanshan Li, Yujing Cui, Zhaolei Zhang, Qiuyu Chen, Ling Lin, Xiandong Lin, Gen Front Immunol Immunology BACKGROUND: Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are critical for immune suppression by restricting immune cell infiltration in the tumor stromal zones from penetrating tumor islands and changing their function status, particularly for CD8(+) T cells. However, assessing and quantifying the impact of CAFs on immune cells and investigating how this impact is related to clinical outcomes, especially the efficacy of immunotherapy, remain unclear. MATERIALS AND METHODS: The TME was characterized using immunohistochemical (IHC) analysis using a large-scale sample size of gene expression profiles. The CD8(+) T cell/CAF ratio (CFR) association with survival was investigated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) lung cancer cohorts. The correlation between CFR and immunotherapeutic efficacy was computed in five independent cohorts. The correlation between CFR and objective response rates (ORRs) following pembrolizumab monotherapy was investigated in 20 solid tumor types. To facilitate clinical translation, the IHC-detected CD8/α-SMA ratio was applied as an immunotherapeutic predictive biomarker in a real-world lung cancer cohort. RESULTS: Compared with normal tissue, CAFs were enriched in cancer tissue, and the amount of CAFs was overwhelmingly higher than that in other immune cells. CAFs are positively correlated with the extent of immune infiltration. A higher CFR was strongly associated with improved survival in lung cancer, melanoma, and urothelial cancer immunotherapy cohorts. Within most cohorts, there was no clear evidence for an association between CFR and programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB). Compared with TMB and PD-L1, a higher correlation coefficient was observed between CFR and the ORR following pembrolizumab monotherapy in 20 solid tumor types (Spearman’s r = 0.69 vs. 0.44 and 0.21). In a real-world cohort, patients with a high CFR detected by IHC benefited considerably from immunotherapy as compared with those with a low CFR (hazard ratio, 0.37; 95% confidence interval, 0.19–0.75; p < 0.001). CONCLUSIONS: CFR is a newly found and simple parameter that can be used for identifying patients unlikely to benefit from immunotherapy. Future studies are needed to confirm this finding. Frontiers Media S.A. 2022-11-09 /pmc/articles/PMC9682254/ /pubmed/36439099 http://dx.doi.org/10.3389/fimmu.2022.974265 Text en Copyright © 2022 Zheng, Jiang, Xiao, Zeng, Peng, Bai, Chen, Li, Zhang, Zheng, Miao, Wang, Wu, Xu, Xu, Li, Li, Gao, Zheng, Li, Wang, Zhou, Xia, Yang, Li, Cui, Zhang, Chen, Lin and Lin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zheng, Xinlong
Jiang, Kan
Xiao, Weijin
Zeng, Dongqiang
Peng, Wenying
Bai, Jing
Chen, Xiaohui
Li, Pansong
Zhang, Longfeng
Zheng, Xiaobin
Miao, Qian
Wang, Haibo
Wu, Shiwen
Xu, Yiquan
Xu, Haipeng
Li, Chao
Li, Lifeng
Gao, Xuan
Zheng, Suya
Li, Junhui
Wang, Deqiang
Zhou, Zhipeng
Xia, Xuefeng
Yang, Shanshan
Li, Yujing
Cui, Zhaolei
Zhang, Qiuyu
Chen, Ling
Lin, Xiandong
Lin, Gen
CD8(+) T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types
title CD8(+) T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types
title_full CD8(+) T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types
title_fullStr CD8(+) T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types
title_full_unstemmed CD8(+) T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types
title_short CD8(+) T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types
title_sort cd8(+) t cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9682254/
https://www.ncbi.nlm.nih.gov/pubmed/36439099
http://dx.doi.org/10.3389/fimmu.2022.974265
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