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Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment

The incidence and mortality of colorectal cancer (CRC) are increasing year by year. The accurate classification of CRC can realize the purpose of personalized and precise treatment for patients. The tumor microenvironment (TME) plays an important role in the malignant progression and immunotherapy o...

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Autores principales: Zheng, Xiaoyong, Ma, Yajie, Bai, Yan, Huang, Tao, Lv, Xuefeng, Deng, Jinhai, Wang, Zhongquan, Lian, Wenping, Tong, Yalin, Zhang, Xinyu, Yue, Miaomiao, Zhang, Yan, Li, Lifeng, Peng, Mengle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9650243/
https://www.ncbi.nlm.nih.gov/pubmed/36389763
http://dx.doi.org/10.3389/fimmu.2022.984480
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author Zheng, Xiaoyong
Ma, Yajie
Bai, Yan
Huang, Tao
Lv, Xuefeng
Deng, Jinhai
Wang, Zhongquan
Lian, Wenping
Tong, Yalin
Zhang, Xinyu
Yue, Miaomiao
Zhang, Yan
Li, Lifeng
Peng, Mengle
author_facet Zheng, Xiaoyong
Ma, Yajie
Bai, Yan
Huang, Tao
Lv, Xuefeng
Deng, Jinhai
Wang, Zhongquan
Lian, Wenping
Tong, Yalin
Zhang, Xinyu
Yue, Miaomiao
Zhang, Yan
Li, Lifeng
Peng, Mengle
author_sort Zheng, Xiaoyong
collection PubMed
description The incidence and mortality of colorectal cancer (CRC) are increasing year by year. The accurate classification of CRC can realize the purpose of personalized and precise treatment for patients. The tumor microenvironment (TME) plays an important role in the malignant progression and immunotherapy of CRC. An in-depth understanding of the clusters based on the TME is of great significance for the discovery of new therapeutic targets for CRC. We extracted data on CRC, including gene expression profile, DNA methylation array, somatic mutations, clinicopathological information, and copy number variation (CNV), from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) (four datasets—GSE14333, GSE17538, GSE38832, and GSE39582), cBioPortal, and FireBrowse. The MCPcounter was utilized to quantify the abundance of 10 TME cells for CRC samples. Cluster repetitive analysis was based on the Hcluster function of the Pheatmap package in R. The ESTIMATE package was applied to compute immune and stromal scores for CRC patients. PCA analysis was used to remove batch effects among different datasets and transform genome-wide DNA methylation profiling into methylation of tumor-infiltrating lymphocyte (MeTIL). We evaluated the mutation differences of the clusters using MOVICS, DeconstructSigs, and GISTIC packages. As for therapy, TIDE and SubMap analyses were carried out to forecast the immunotherapy response of the clusters, and chemotherapeutic sensibility was estimated based on the pRRophetic package. All results were verified in the TCGA and GEO data. Four immune clusters (ImmClust-CS1, ImmClust-CS2, ImmClust-CS3, and ImmClust-CS4) were identified for CRC. The four ImmClusts exhibited distinct TME compositions, cancer-associated fibroblasts (CAFs), functional orientation, and immune checkpoints. The highest immune, stromal, and MeTIL scores were observed in CS2, in contrast to the lowest scores in CS4. CS1 may respond to immunotherapy, while CS2 may respond to immunotherapy after anti-CAFs. Among the four ImmClusts, the top 15 markers with the highest mutation frequency were acquired, and CS1 had significantly lower CNA on the focal level than other subtypes. In addition, CS1 and CS2 patients had more stable chromosomes than CS3 and CS4. The most sensitive chemotherapeutic agents in these four ImmClusts were also found. IHC results revealed that CD29 stained significantly darker in the cancer samples, indicating that their CD29 was highly expressed in colon cancer. This work revealed the novel clusters based on TME for CRC, which would guide in predicting the prognosis, biological features, and appropriate treatment for patients with CRC.
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spelling pubmed-96502432022-11-15 Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment Zheng, Xiaoyong Ma, Yajie Bai, Yan Huang, Tao Lv, Xuefeng Deng, Jinhai Wang, Zhongquan Lian, Wenping Tong, Yalin Zhang, Xinyu Yue, Miaomiao Zhang, Yan Li, Lifeng Peng, Mengle Front Immunol Immunology The incidence and mortality of colorectal cancer (CRC) are increasing year by year. The accurate classification of CRC can realize the purpose of personalized and precise treatment for patients. The tumor microenvironment (TME) plays an important role in the malignant progression and immunotherapy of CRC. An in-depth understanding of the clusters based on the TME is of great significance for the discovery of new therapeutic targets for CRC. We extracted data on CRC, including gene expression profile, DNA methylation array, somatic mutations, clinicopathological information, and copy number variation (CNV), from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) (four datasets—GSE14333, GSE17538, GSE38832, and GSE39582), cBioPortal, and FireBrowse. The MCPcounter was utilized to quantify the abundance of 10 TME cells for CRC samples. Cluster repetitive analysis was based on the Hcluster function of the Pheatmap package in R. The ESTIMATE package was applied to compute immune and stromal scores for CRC patients. PCA analysis was used to remove batch effects among different datasets and transform genome-wide DNA methylation profiling into methylation of tumor-infiltrating lymphocyte (MeTIL). We evaluated the mutation differences of the clusters using MOVICS, DeconstructSigs, and GISTIC packages. As for therapy, TIDE and SubMap analyses were carried out to forecast the immunotherapy response of the clusters, and chemotherapeutic sensibility was estimated based on the pRRophetic package. All results were verified in the TCGA and GEO data. Four immune clusters (ImmClust-CS1, ImmClust-CS2, ImmClust-CS3, and ImmClust-CS4) were identified for CRC. The four ImmClusts exhibited distinct TME compositions, cancer-associated fibroblasts (CAFs), functional orientation, and immune checkpoints. The highest immune, stromal, and MeTIL scores were observed in CS2, in contrast to the lowest scores in CS4. CS1 may respond to immunotherapy, while CS2 may respond to immunotherapy after anti-CAFs. Among the four ImmClusts, the top 15 markers with the highest mutation frequency were acquired, and CS1 had significantly lower CNA on the focal level than other subtypes. In addition, CS1 and CS2 patients had more stable chromosomes than CS3 and CS4. The most sensitive chemotherapeutic agents in these four ImmClusts were also found. IHC results revealed that CD29 stained significantly darker in the cancer samples, indicating that their CD29 was highly expressed in colon cancer. This work revealed the novel clusters based on TME for CRC, which would guide in predicting the prognosis, biological features, and appropriate treatment for patients with CRC. Frontiers Media S.A. 2022-10-28 /pmc/articles/PMC9650243/ /pubmed/36389763 http://dx.doi.org/10.3389/fimmu.2022.984480 Text en Copyright © 2022 Zheng, Ma, Bai, Huang, Lv, Deng, Wang, Lian, Tong, Zhang, Yue, Zhang, Li and Peng 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, Xiaoyong
Ma, Yajie
Bai, Yan
Huang, Tao
Lv, Xuefeng
Deng, Jinhai
Wang, Zhongquan
Lian, Wenping
Tong, Yalin
Zhang, Xinyu
Yue, Miaomiao
Zhang, Yan
Li, Lifeng
Peng, Mengle
Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment
title Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment
title_full Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment
title_fullStr Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment
title_full_unstemmed Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment
title_short Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment
title_sort identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9650243/
https://www.ncbi.nlm.nih.gov/pubmed/36389763
http://dx.doi.org/10.3389/fimmu.2022.984480
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