Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis
Background The combination of immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced gastric cancer (GC). It is crucial to unravel chemotherapy-induced tumor microenvironment (TME) modulation and identify which immunotherapy would improve antitumor effect.Methods In...
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003984.full |
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| author | Jian Zhang Xiaomei Li Ying Hu Bin Dong Yongning Jia Ziyu Li Xiaojing Cheng Jinyao Shi Jiafu Ji Zhongwu Li Hong Du Ting Guo Shuqin Jia Xiaofang Xing Yunsheng Dou |
| author_facet | Jian Zhang Xiaomei Li Ying Hu Bin Dong Yongning Jia Ziyu Li Xiaojing Cheng Jinyao Shi Jiafu Ji Zhongwu Li Hong Du Ting Guo Shuqin Jia Xiaofang Xing Yunsheng Dou |
| author_sort | Jian Zhang |
| collection | DOAJ |
| description | Background The combination of immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced gastric cancer (GC). It is crucial to unravel chemotherapy-induced tumor microenvironment (TME) modulation and identify which immunotherapy would improve antitumor effect.Methods In this study, tumor-associated immune cells (TAICs) infiltration in residual tumor after neoadjuvant chemotherapy (NAC) together with 1075 cases of treatment-naïve GC patients was analyzed first. Then we performed multiplex fluorescence staining of a panel of immune markers (CD3, CD4, CD8, FOXP3 and PDL1) and T cell receptor β-chain sequencing to phenotype and enumerate T cell subpopulations and clonal expansion in paired GC samples (prechemotherapy and postchemotherapy) from another cohort of 30 cases of stage II/III GC patients.Results Infiltration of CD68+ macrophages in residual tumors after NAC was significantly decreased compared with treatment-naïve GC patients, while no significant difference observed with respect to other immune markers. In residual tumors, post-NAC CD8 +T cells and CD68+ macrophages levels were significantly associated with chemotherapy response. Post-NAC CD8+ T cell levels remained as an independent predictor for favorable prognosis. Furthermore, when comparing the paired samples before and after NAC from 30 cases of stage II/III GC patients, we found FOXP3+ regulatory T cells proportion significantly decreased after chemotherapy. Pre-NAC FOXP3+ T reg cells level was much richer in the response group and decreased more significantly in the stromal compartment. CD8+ cytotoxic T lymphocytes levels were elevated after chemotherapy, which was more significant in the group treated with XELOX regimen and in patients with better response, consistent with the TCR diversity elevation.Conclusions These findings have deepened our understanding of the immune modulating effect of chemotherapy and suggest that the immune profile of specimens after standard chemotherapy should be considered for the personalized immunotherapy to ultimately improve clinical outcome in patients with GC. |
| format | Article |
| id | doaj-art-79db357f68524c2292cde109b332630a |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-79db357f68524c2292cde109b332630a2025-02-02T23:00:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003984Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysisJian Zhang0Xiaomei Li1Ying Hu2Bin Dong3Yongning Jia4Ziyu Li5Xiaojing Cheng6Jinyao Shi7Jiafu Ji8Zhongwu Li9Hong Du10Ting Guo11Shuqin Jia12Xiaofang Xing13Yunsheng Dou145Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Rheumatology and Immunology, Anhui Provincial Hospital, Hefei, Anhui, ChinaDepartment of Magnetic Resonance Imaging (MRI), The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, ChinaDepartment of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, ChinaDepartment of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China3 Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, ChinaDepartment of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, ChinaDepartment of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, ChinaDepartment of Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, ChinaAcademy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, ChinaBackground The combination of immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced gastric cancer (GC). It is crucial to unravel chemotherapy-induced tumor microenvironment (TME) modulation and identify which immunotherapy would improve antitumor effect.Methods In this study, tumor-associated immune cells (TAICs) infiltration in residual tumor after neoadjuvant chemotherapy (NAC) together with 1075 cases of treatment-naïve GC patients was analyzed first. Then we performed multiplex fluorescence staining of a panel of immune markers (CD3, CD4, CD8, FOXP3 and PDL1) and T cell receptor β-chain sequencing to phenotype and enumerate T cell subpopulations and clonal expansion in paired GC samples (prechemotherapy and postchemotherapy) from another cohort of 30 cases of stage II/III GC patients.Results Infiltration of CD68+ macrophages in residual tumors after NAC was significantly decreased compared with treatment-naïve GC patients, while no significant difference observed with respect to other immune markers. In residual tumors, post-NAC CD8 +T cells and CD68+ macrophages levels were significantly associated with chemotherapy response. Post-NAC CD8+ T cell levels remained as an independent predictor for favorable prognosis. Furthermore, when comparing the paired samples before and after NAC from 30 cases of stage II/III GC patients, we found FOXP3+ regulatory T cells proportion significantly decreased after chemotherapy. Pre-NAC FOXP3+ T reg cells level was much richer in the response group and decreased more significantly in the stromal compartment. CD8+ cytotoxic T lymphocytes levels were elevated after chemotherapy, which was more significant in the group treated with XELOX regimen and in patients with better response, consistent with the TCR diversity elevation.Conclusions These findings have deepened our understanding of the immune modulating effect of chemotherapy and suggest that the immune profile of specimens after standard chemotherapy should be considered for the personalized immunotherapy to ultimately improve clinical outcome in patients with GC.https://jitc.bmj.com/content/10/3/e003984.full |
| spellingShingle | Jian Zhang Xiaomei Li Ying Hu Bin Dong Yongning Jia Ziyu Li Xiaojing Cheng Jinyao Shi Jiafu Ji Zhongwu Li Hong Du Ting Guo Shuqin Jia Xiaofang Xing Yunsheng Dou Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis Journal for ImmunoTherapy of Cancer |
| title | Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis |
| title_full | Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis |
| title_fullStr | Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis |
| title_full_unstemmed | Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis |
| title_short | Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis |
| title_sort | effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and t cell receptor repertoire analysis |
| url | https://jitc.bmj.com/content/10/3/e003984.full |
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