CD8+ T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types
BackgroundCancer-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, ass...
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.974265/full |
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| author | Xinlong Zheng Kan Jiang Weijin Xiao Dongqiang Zeng Wenying Peng Jing Bai Xiaohui Chen Pansong Li Longfeng Zhang Xiaobin Zheng Qian Miao Haibo Wang Shiwen Wu Yiquan Xu Haipeng Xu Chao Li Lifeng Li Xuan Gao Suya Zheng Junhui Li Deqiang Wang Zhipeng Zhou Xuefeng Xia Shanshan Yang Yujing Li Zhaolei Cui Qiuyu Zhang Ling Chen Xiandong Lin Gen Lin |
| author_facet | Xinlong Zheng Kan Jiang Weijin Xiao Dongqiang Zeng Wenying Peng Jing Bai Xiaohui Chen Pansong Li Longfeng Zhang Xiaobin Zheng Qian Miao Haibo Wang Shiwen Wu Yiquan Xu Haipeng Xu Chao Li Lifeng Li Xuan Gao Suya Zheng Junhui Li Deqiang Wang Zhipeng Zhou Xuefeng Xia Shanshan Yang Yujing Li Zhaolei Cui Qiuyu Zhang Ling Chen Xiandong Lin Gen Lin |
| author_sort | Xinlong Zheng |
| collection | DOAJ |
| description | BackgroundCancer-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 methodsThe 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.ResultsCompared 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).ConclusionsCFR 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. |
| first_indexed | 2024-04-13T22:00:07Z |
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| language | English |
| last_indexed | 2024-04-13T22:00:07Z |
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| series | Frontiers in Immunology |
| spelling | doaj.art-498279893fb04ef4899aa04420545ced2022-12-22T02:28:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-11-011310.3389/fimmu.2022.974265974265CD8+ T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer typesXinlong Zheng0Kan Jiang1Weijin Xiao2Dongqiang Zeng3Wenying Peng4Jing Bai5Xiaohui Chen6Pansong Li7Longfeng Zhang8Xiaobin Zheng9Qian Miao10Haibo Wang11Shiwen Wu12Yiquan Xu13Haipeng Xu14Chao Li15Lifeng Li16Xuan Gao17Suya Zheng18Junhui Li19Deqiang Wang20Zhipeng Zhou21Xuefeng Xia22Shanshan Yang23Yujing Li24Zhaolei Cui25Qiuyu Zhang26Ling Chen27Xiandong Lin28Gen Lin29Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Pathology, College of Clinical Medicine for Oncology, Fujian Medical University, Fuzhou, ChinaDepartment of Oncology, Southern Medical University, Guangzhou, ChinaThe Second Department of Oncology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, Kunming, ChinaR&D Department, Geneplus-Beijing Institute, Beijing, ChinaDepartment of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, ChinaR&D Department, Geneplus-Beijing Institute, Beijing, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Pathology, College of Clinical Medicine for Oncology, Fujian Medical University, Fuzhou, ChinaR&D Department, Geneplus-Beijing Institute, Beijing, ChinaR&D Department, Geneplus-Beijing Institute, Beijing, ChinaChinese People’s Liberation Army 92403 Unit Support Department, Navy Fujian Base Hospital, Fuzhou, ChinaDepartment of Medical Genetics and Genomics, National Protein Science Center, Beijing, ChinaDepartment of Medical Oncology, Cancer Therapy Center, Affiliated Hospital of Jiangsu University, Zhenjiang, ChinaR&D Department, Geneplus-Beijing Institute, Beijing, ChinaR&D Department, Geneplus-Beijing Institute, Beijing, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, China0Laboratory of Biochemistry and Molecular Biology Research, Department of Clinical Laboratory, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, China1Institute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China1Institute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China2Laboratory of Radiation Oncology and Radiobiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, ChinaDepartment of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, ChinaBackgroundCancer-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 methodsThe 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.ResultsCompared 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).ConclusionsCFR 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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.974265/fullCD8+ T cellcancer-associated fibroblastprognostic biomarkerpredictive biomarkerimmunotherapy |
| spellingShingle | Xinlong Zheng Kan Jiang Weijin Xiao Dongqiang Zeng Wenying Peng Jing Bai Xiaohui Chen Pansong Li Longfeng Zhang Xiaobin Zheng Qian Miao Haibo Wang Shiwen Wu Yiquan Xu Haipeng Xu Chao Li Lifeng Li Xuan Gao Suya Zheng Junhui Li Deqiang Wang Zhipeng Zhou Xuefeng Xia Shanshan Yang Yujing Li Zhaolei Cui Qiuyu Zhang Ling Chen Xiandong Lin Gen Lin CD8+ T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types Frontiers in Immunology CD8+ T cell cancer-associated fibroblast prognostic biomarker predictive biomarker immunotherapy |
| 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 | CD8+ T cell cancer-associated fibroblast prognostic biomarker predictive biomarker immunotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.974265/full |
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