Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes
Background and aimsImmunologically hot tumors, characterized by an inflamed tumor microenvironment (TME), contrast significantly with immunologically cold tumors. The identification of these tumor immune subtypes holds clinical significance, as hot tumors may exhibit improved prognoses and heightene...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1382842/full |
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| author | Mengmeng Sang Jia Ge Juan Ge Juan Ge Gu Tang Qiwen Wang Jiarun Wu Liming Mao Liming Mao Xiaoling Ding Xiaorong Zhou |
| author_facet | Mengmeng Sang Jia Ge Juan Ge Juan Ge Gu Tang Qiwen Wang Jiarun Wu Liming Mao Liming Mao Xiaoling Ding Xiaorong Zhou |
| author_sort | Mengmeng Sang |
| collection | DOAJ |
| description | Background and aimsImmunologically hot tumors, characterized by an inflamed tumor microenvironment (TME), contrast significantly with immunologically cold tumors. The identification of these tumor immune subtypes holds clinical significance, as hot tumors may exhibit improved prognoses and heightened responsiveness to checkpoint blockade therapy. Nevertheless, as yet there is no consensus regarding the clinically relevant definition of hot/cold tumors, and the influence of immune genes on the formation of hot/cold tumors remains poorly understood.MethodsData for 33 different types of cancer were obtained from The Cancer Genome Atlas database, and their immune composition was assessed using the CIBERSORT algorithm. Tumors were categorized as either hot or cold based on their distinct immune composition, ongoing immune response, and overall survival. A customized immunogram was created to identify important immunological characteristics. Kyoto Encyclopedia of Genes and Genomes and Hallmark pathway enrichment were evaluated through gene set variation analysis. Additionally, hub genes that regulate the tumor microenvironment were identified, and their expression patterns were analyzed using single-cell RNA sequencing. Furthermore, drug sensitivity and molecular docking analyses were performed to identify potential drug candidates capable of transforming cold tumors into hot tumors. For validation, a clinical cohort of patients diagnosed with pancreatic adenocarcinoma was examined using multiplex immunohistochemistry.ResultsWe were able to differentiate between hot and cold tumors in various types of cancer (bladder urothelial carcinoma, pancreatic adenocarcinoma, and cervical squamous cell carcinoma) by analyzing the presence of CD8+ T cells, activated natural killer cells, and M2-type macrophages, as well as the cytolytic activity and T cell proliferation. Hub genes that regulate the TME, including PDCD1, CD276, and NT5E, were discovered. The increased expression of NT5E and its prognostic significance were confirmed through multiplex immunohistochemistry in pancreatic adenocarcinoma. Finally, dasatinib and tozasertib were identified as drug candidates capable of converting cold pancreatic adenocarcinoma tumors into hot tumors.ConclusionIn this study, we developed a framework for discerning clinically significant immune subtypes across various cancer types, further identifying several potential targets for converting cold tumors into hot tumors to enhance anticancer treatment efficacy. |
| format | Article |
| id | doaj-art-41eb49565c6b440c9fdb6ad84811d898 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-41eb49565c6b440c9fdb6ad84811d8982025-01-22T07:12:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.13828421382842Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomesMengmeng Sang0Jia Ge1Juan Ge2Juan Ge3Gu Tang4Qiwen Wang5Jiarun Wu6Liming Mao7Liming Mao8Xiaoling Ding9Xiaorong Zhou10Department of Immunology, School of Medicine, Nantong University, Nantong, ChinaDepartment of Immunology, School of Medicine, Nantong University, Nantong, ChinaDepartment of Immunology, School of Medicine, Nantong University, Nantong, ChinaDepartment of Respiratory Medicine, Affiliated Nantong Hospital of Shanghai University, Nantong, ChinaDepartment of Immunology, School of Medicine, Nantong University, Nantong, ChinaDepartment of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, ChinaDepartment of Immunology, School of Medicine, Nantong University, Nantong, ChinaDepartment of Immunology, School of Medicine, Nantong University, Nantong, ChinaBasic Medical Research Center, School of Medicine, Nantong University, Nantong, ChinaDepartment of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, ChinaDepartment of Immunology, School of Medicine, Nantong University, Nantong, ChinaBackground and aimsImmunologically hot tumors, characterized by an inflamed tumor microenvironment (TME), contrast significantly with immunologically cold tumors. The identification of these tumor immune subtypes holds clinical significance, as hot tumors may exhibit improved prognoses and heightened responsiveness to checkpoint blockade therapy. Nevertheless, as yet there is no consensus regarding the clinically relevant definition of hot/cold tumors, and the influence of immune genes on the formation of hot/cold tumors remains poorly understood.MethodsData for 33 different types of cancer were obtained from The Cancer Genome Atlas database, and their immune composition was assessed using the CIBERSORT algorithm. Tumors were categorized as either hot or cold based on their distinct immune composition, ongoing immune response, and overall survival. A customized immunogram was created to identify important immunological characteristics. Kyoto Encyclopedia of Genes and Genomes and Hallmark pathway enrichment were evaluated through gene set variation analysis. Additionally, hub genes that regulate the tumor microenvironment were identified, and their expression patterns were analyzed using single-cell RNA sequencing. Furthermore, drug sensitivity and molecular docking analyses were performed to identify potential drug candidates capable of transforming cold tumors into hot tumors. For validation, a clinical cohort of patients diagnosed with pancreatic adenocarcinoma was examined using multiplex immunohistochemistry.ResultsWe were able to differentiate between hot and cold tumors in various types of cancer (bladder urothelial carcinoma, pancreatic adenocarcinoma, and cervical squamous cell carcinoma) by analyzing the presence of CD8+ T cells, activated natural killer cells, and M2-type macrophages, as well as the cytolytic activity and T cell proliferation. Hub genes that regulate the TME, including PDCD1, CD276, and NT5E, were discovered. The increased expression of NT5E and its prognostic significance were confirmed through multiplex immunohistochemistry in pancreatic adenocarcinoma. Finally, dasatinib and tozasertib were identified as drug candidates capable of converting cold pancreatic adenocarcinoma tumors into hot tumors.ConclusionIn this study, we developed a framework for discerning clinically significant immune subtypes across various cancer types, further identifying several potential targets for converting cold tumors into hot tumors to enhance anticancer treatment efficacy.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1382842/fulltumor microenvironmentpan-cancerhot/cold tumorsimmunotherapypancreatic adenocarcinoma |
| spellingShingle | Mengmeng Sang Jia Ge Juan Ge Juan Ge Gu Tang Qiwen Wang Jiarun Wu Liming Mao Liming Mao Xiaoling Ding Xiaorong Zhou Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes Frontiers in Immunology tumor microenvironment pan-cancer hot/cold tumors immunotherapy pancreatic adenocarcinoma |
| title | Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes |
| title_full | Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes |
| title_fullStr | Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes |
| title_full_unstemmed | Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes |
| title_short | Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes |
| title_sort | immune regulatory genes impact the hot cold tumor microenvironment affecting cancer treatment and patient outcomes |
| topic | tumor microenvironment pan-cancer hot/cold tumors immunotherapy pancreatic adenocarcinoma |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1382842/full |
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