A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors

Background: The immunotherapy efficacy in gastric cancer (GC) is limited. Cancer-associated fibroblasts (CAFs) induce primary resistance to immunotherapy. However, CAF infiltration in tumors is difficult to evaluate due to the lack of validated and standardized quantified methods. This study aimed t...

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Autores principales: Lu, Yi, Li, Dan, Cao, Yixin, Ying, Leqian, Tao, Qing, Xiong, Fen, Hu, Zhangmin, Yang, Yufei, Qiao, Xuehan, Peng, Chen, Zhu, Dongqin, Wang, Deqiang, Li, Xiaoqin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087633/
https://www.ncbi.nlm.nih.gov/pubmed/35557959
http://dx.doi.org/10.3389/fcell.2022.862294
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author Lu, Yi
Li, Dan
Cao, Yixin
Ying, Leqian
Tao, Qing
Xiong, Fen
Hu, Zhangmin
Yang, Yufei
Qiao, Xuehan
Peng, Chen
Zhu, Dongqin
Wang, Deqiang
Li, Xiaoqin
author_facet Lu, Yi
Li, Dan
Cao, Yixin
Ying, Leqian
Tao, Qing
Xiong, Fen
Hu, Zhangmin
Yang, Yufei
Qiao, Xuehan
Peng, Chen
Zhu, Dongqin
Wang, Deqiang
Li, Xiaoqin
author_sort Lu, Yi
collection PubMed
description Background: The immunotherapy efficacy in gastric cancer (GC) is limited. Cancer-associated fibroblasts (CAFs) induce primary resistance to immunotherapy. However, CAF infiltration in tumors is difficult to evaluate due to the lack of validated and standardized quantified methods. This study aimed to investigate the impact of infiltrating CAFs alternatively using fibroblast-associated mutation scoring (FAMscore). Methods: In a GC cohort from Affiliated Hospital of Jiangsu University (AHJU), whole exon sequencing of genomic mutations, whole transcriptome sequencing of mRNA expression profiles, and immunofluorescence staining of tumor-infiltrating immune cells were performed. GC data from The Cancer Genome Atlas were used to identify genetic mutations which were associated with overall survival (OS) and impacted infiltrating CAF abundance determined by transcriptome-based estimation. FAMscore was then constructed through a least absolute shrinkage and selection operator Cox regression model and further validated in AHJU. The predictive role of FAMscore for immunotherapy outcomes was tested in 1 GC, one melanoma, and two non-small-cell lung cancer (NSCLC-1 and -2) cohorts wherein participants were treated by immune checkpoint inhibitors. Results: FAMscore was calculated based on a mutation signature consisting of 16 genes. In both TCGA and AHJU, a high FAMscore was an independent predictor for poor OS of GC patients. FAMscore was associated with immune-associated genome biomarkers, immune cell infiltration, and signaling pathways of abnormal immunity. Importantly, patients with high FAMscore presented inferiority in the objective response rate of immunotherapy compared to those with low FAMscore, with 14.6% vs. 66.7% (p<0.001) in GC, 19.6% vs. 68.2% (p<0.001) in NSCLC-1, 23.1% vs 75% (p = 0.007) in NSCLC-2, and 40.9% vs 75% (p = 0.037) in melanoma. For available survival data, a high FAMscore was also an independent predictor of poor progression-free survival in NSCLC-1 (HR = 2.55, 95% CI: 1.16–5.62, p = 0.02) and NSCLC-2 (HR = 5.0, 95% CI: 1.13–22.19, p = 0.034) and poor OS in melanoma (HR = 3.48, 95% CI: 1.27–9.55, p = 0.015). Conclusions: Alternative evaluation of CAF infiltration in GC by determining the FAMscore could independently predict prognosis and immunotherapy outcomes. The FAMscore may be used to optimize patient selection for immunotherapy.
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spelling pubmed-90876332022-05-11 A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors Lu, Yi Li, Dan Cao, Yixin Ying, Leqian Tao, Qing Xiong, Fen Hu, Zhangmin Yang, Yufei Qiao, Xuehan Peng, Chen Zhu, Dongqin Wang, Deqiang Li, Xiaoqin Front Cell Dev Biol Cell and Developmental Biology Background: The immunotherapy efficacy in gastric cancer (GC) is limited. Cancer-associated fibroblasts (CAFs) induce primary resistance to immunotherapy. However, CAF infiltration in tumors is difficult to evaluate due to the lack of validated and standardized quantified methods. This study aimed to investigate the impact of infiltrating CAFs alternatively using fibroblast-associated mutation scoring (FAMscore). Methods: In a GC cohort from Affiliated Hospital of Jiangsu University (AHJU), whole exon sequencing of genomic mutations, whole transcriptome sequencing of mRNA expression profiles, and immunofluorescence staining of tumor-infiltrating immune cells were performed. GC data from The Cancer Genome Atlas were used to identify genetic mutations which were associated with overall survival (OS) and impacted infiltrating CAF abundance determined by transcriptome-based estimation. FAMscore was then constructed through a least absolute shrinkage and selection operator Cox regression model and further validated in AHJU. The predictive role of FAMscore for immunotherapy outcomes was tested in 1 GC, one melanoma, and two non-small-cell lung cancer (NSCLC-1 and -2) cohorts wherein participants were treated by immune checkpoint inhibitors. Results: FAMscore was calculated based on a mutation signature consisting of 16 genes. In both TCGA and AHJU, a high FAMscore was an independent predictor for poor OS of GC patients. FAMscore was associated with immune-associated genome biomarkers, immune cell infiltration, and signaling pathways of abnormal immunity. Importantly, patients with high FAMscore presented inferiority in the objective response rate of immunotherapy compared to those with low FAMscore, with 14.6% vs. 66.7% (p<0.001) in GC, 19.6% vs. 68.2% (p<0.001) in NSCLC-1, 23.1% vs 75% (p = 0.007) in NSCLC-2, and 40.9% vs 75% (p = 0.037) in melanoma. For available survival data, a high FAMscore was also an independent predictor of poor progression-free survival in NSCLC-1 (HR = 2.55, 95% CI: 1.16–5.62, p = 0.02) and NSCLC-2 (HR = 5.0, 95% CI: 1.13–22.19, p = 0.034) and poor OS in melanoma (HR = 3.48, 95% CI: 1.27–9.55, p = 0.015). Conclusions: Alternative evaluation of CAF infiltration in GC by determining the FAMscore could independently predict prognosis and immunotherapy outcomes. The FAMscore may be used to optimize patient selection for immunotherapy. Frontiers Media S.A. 2022-04-26 /pmc/articles/PMC9087633/ /pubmed/35557959 http://dx.doi.org/10.3389/fcell.2022.862294 Text en Copyright © 2022 Lu, Li, Cao, Ying, Tao, Xiong, Hu, Yang, Qiao, Peng, Zhu, Wang and Li. 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 Cell and Developmental Biology
Lu, Yi
Li, Dan
Cao, Yixin
Ying, Leqian
Tao, Qing
Xiong, Fen
Hu, Zhangmin
Yang, Yufei
Qiao, Xuehan
Peng, Chen
Zhu, Dongqin
Wang, Deqiang
Li, Xiaoqin
A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors
title A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors
title_full A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors
title_fullStr A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors
title_full_unstemmed A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors
title_short A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors
title_sort genomic signature reflecting fibroblast infiltration into gastric cancer is associated with prognosis and treatment outcomes of immune checkpoint inhibitors
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087633/
https://www.ncbi.nlm.nih.gov/pubmed/35557959
http://dx.doi.org/10.3389/fcell.2022.862294
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