TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy
IntroductionThe ErbB-2.1(TOB1) signaling transducer protein is a tumor-suppressive protein that actively suppresses the malignant phenotype of gastric cancer cells. Yet, TOB1 negatively regulates the activation and growth of different immune cells. Understanding the expression and role of TOB1 in th...
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| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1369087/full |
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| author | Jinfeng Zhang Yunlong Li Jing Chen Tongtong Huang Jing Lin Yilin Pi Huiting Hao Dong Wang Xiao Liang Songbin Fu Jingcui Yu Jingcui Yu |
| author_facet | Jinfeng Zhang Yunlong Li Jing Chen Tongtong Huang Jing Lin Yilin Pi Huiting Hao Dong Wang Xiao Liang Songbin Fu Jingcui Yu Jingcui Yu |
| author_sort | Jinfeng Zhang |
| collection | DOAJ |
| description | IntroductionThe ErbB-2.1(TOB1) signaling transducer protein is a tumor-suppressive protein that actively suppresses the malignant phenotype of gastric cancer cells. Yet, TOB1 negatively regulates the activation and growth of different immune cells. Understanding the expression and role of TOB1 in the gastric cancer immune environment is crucial to maximize its potential in targeted immunotherapy.MethodsThis study employed multiplex immunofluorescence analysis to precisely delineate and quantify the expression of TOB1 in immune cells within gastric cancer tissue microarrays. Univariate and multivariate Cox analyses were performed to assess the influence of clinical-pathological parameters, immune cells, TOB1, and double-positive cells on the prognosis of gastric cancer patients. Subsequent experiments included co-culture assays of si-TOB1-transfected neutrophils with AGS or HGC-27 cells, along with EdU, invasion, migration assays, and bioinformatics analyses, aimed at elucidating the mechanisms through which TOB1 in neutrophils impacts the prognosis of gastric cancer patients.ResultsWe remarkably revealed that TOB1 exhibits varying expression levels in both the nucleus (nTOB1) and cytoplasm (cTOB1) of diverse immune cell populations, including CD8+ T cells, CD66b+ neutrophils, FOXP3+ Tregs, CD20+ B cells, CD4+ T cells, and CD68+ macrophages within gastric cancer and paracancerous tissues. Significantly, TOB1 was notably concentrated in CD66b+ neutrophils. Survival analysis showed that a higher density of cTOB1/nTOB1+CD66b+ neutrophils was linked to a better prognosis. Subsequent experiments revealed that, following stimulation with the supernatant of tumor tissue culture, the levels of TOB1 protein and mRNA in neutrophils decreased, accompanied by enhanced apoptosis. HL-60 cells were successfully induced to neutrophil-like cells by DMSO. Neutrophils-like cells with attenuated TOB1 gene expression by si-TOB1 demonstrated heightened apoptosis, consequently fostering a malignant phenotype in AGS and HCG-27 cells upon co-cultivation. The subsequent analysis of the datasets from TCGA and TIMER2 revealed that patients with high levels of TOB1 combined neutrophils showed better immunotherapy response.DiscussionThis study significantly advances our comprehension of TOB1’s role within the immune microenvironment of gastric cancer, offering promising therapeutic targets for immunotherapy in this context. |
| first_indexed | 2024-04-24T17:36:45Z |
| format | Article |
| id | doaj.art-edec4b7adc8c4843b67f0edcbd1c0bb8 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-24T17:36:45Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-edec4b7adc8c4843b67f0edcbd1c0bb82024-03-28T04:39:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-03-011510.3389/fimmu.2024.13690871369087TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacyJinfeng Zhang0Yunlong Li1Jing Chen2Tongtong Huang3Jing Lin4Yilin Pi5Huiting Hao6Dong Wang7Xiao Liang8Songbin Fu9Jingcui Yu10Jingcui Yu11Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaDepartment of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaScientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaScientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaDepartment of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaDepartment of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, ChinaScientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaKey Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin, ChinaKey Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin, ChinaScientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaKey Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin, ChinaIntroductionThe ErbB-2.1(TOB1) signaling transducer protein is a tumor-suppressive protein that actively suppresses the malignant phenotype of gastric cancer cells. Yet, TOB1 negatively regulates the activation and growth of different immune cells. Understanding the expression and role of TOB1 in the gastric cancer immune environment is crucial to maximize its potential in targeted immunotherapy.MethodsThis study employed multiplex immunofluorescence analysis to precisely delineate and quantify the expression of TOB1 in immune cells within gastric cancer tissue microarrays. Univariate and multivariate Cox analyses were performed to assess the influence of clinical-pathological parameters, immune cells, TOB1, and double-positive cells on the prognosis of gastric cancer patients. Subsequent experiments included co-culture assays of si-TOB1-transfected neutrophils with AGS or HGC-27 cells, along with EdU, invasion, migration assays, and bioinformatics analyses, aimed at elucidating the mechanisms through which TOB1 in neutrophils impacts the prognosis of gastric cancer patients.ResultsWe remarkably revealed that TOB1 exhibits varying expression levels in both the nucleus (nTOB1) and cytoplasm (cTOB1) of diverse immune cell populations, including CD8+ T cells, CD66b+ neutrophils, FOXP3+ Tregs, CD20+ B cells, CD4+ T cells, and CD68+ macrophages within gastric cancer and paracancerous tissues. Significantly, TOB1 was notably concentrated in CD66b+ neutrophils. Survival analysis showed that a higher density of cTOB1/nTOB1+CD66b+ neutrophils was linked to a better prognosis. Subsequent experiments revealed that, following stimulation with the supernatant of tumor tissue culture, the levels of TOB1 protein and mRNA in neutrophils decreased, accompanied by enhanced apoptosis. HL-60 cells were successfully induced to neutrophil-like cells by DMSO. Neutrophils-like cells with attenuated TOB1 gene expression by si-TOB1 demonstrated heightened apoptosis, consequently fostering a malignant phenotype in AGS and HCG-27 cells upon co-cultivation. The subsequent analysis of the datasets from TCGA and TIMER2 revealed that patients with high levels of TOB1 combined neutrophils showed better immunotherapy response.DiscussionThis study significantly advances our comprehension of TOB1’s role within the immune microenvironment of gastric cancer, offering promising therapeutic targets for immunotherapy in this context.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1369087/fullTOB1gastric cancerneutrophils apoptosisimmunotherapyimmune cells |
| spellingShingle | Jinfeng Zhang Yunlong Li Jing Chen Tongtong Huang Jing Lin Yilin Pi Huiting Hao Dong Wang Xiao Liang Songbin Fu Jingcui Yu Jingcui Yu TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy Frontiers in Immunology TOB1 gastric cancer neutrophils apoptosis immunotherapy immune cells |
| title | TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy |
| title_full | TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy |
| title_fullStr | TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy |
| title_full_unstemmed | TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy |
| title_short | TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy |
| title_sort | tob1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy |
| topic | TOB1 gastric cancer neutrophils apoptosis immunotherapy immune cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1369087/full |
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