Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer
Background Distant metastasis is the major cause of mortality in patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy. Local radiotherapy can trigger an abscopal response to metastatic tumor cells. However, the abscopal effect is a rare event. CD4+ regulatory T...
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BMJ Publishing Group
2020-07-01
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Series: | Journal for ImmunoTherapy of Cancer |
Online Access: | https://jitc.bmj.com/content/8/2/e000826.full |
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doaj-512ed9f583c74c18aab324cd0728851a |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jin Gu Dengbo Ji Can Song Yongheng Li Jinhong Xia Yanjing Wu Jinying Jia Xinxin Cui Songmao Yu |
spellingShingle |
Jin Gu Dengbo Ji Can Song Yongheng Li Jinhong Xia Yanjing Wu Jinying Jia Xinxin Cui Songmao Yu Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer Journal for ImmunoTherapy of Cancer |
author_facet |
Jin Gu Dengbo Ji Can Song Yongheng Li Jinhong Xia Yanjing Wu Jinying Jia Xinxin Cui Songmao Yu |
author_sort |
Jin Gu |
title |
Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer |
title_short |
Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer |
title_full |
Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer |
title_fullStr |
Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer |
title_full_unstemmed |
Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer |
title_sort |
combination of radiotherapy and suppression of tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2020-07-01 |
description |
Background Distant metastasis is the major cause of mortality in patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy. Local radiotherapy can trigger an abscopal response to metastatic tumor cells. However, the abscopal effect is a rare event. CD4+ regulatory T (Treg) cell is a highly immune-suppressive subset which impedes immune surveillance against cancer, prevents the development of effective antitumor immunity and promotes tumor progression. We assume that the exploitation of the proimmunogenic effects of radiotherapy with anti-CD25 or anti-Cytotoxic T-Lymphocyte Associated Protein 4 (anti-CTLA4) monoclonal antibodies (mAbs) may enhance the local and abscopal effects in rectal cancer and improve the therapeutic outcome.Methods mRNA expression profiling of 81 pretreatment biopsy samples from LARC patients who received neoadjuvant radiotherapy (nRT) was performed to analyze the correlation between gene expression and prognosis. A retrospective analysis of patients with rectal cancer with distant metastasis or synchronous extracolonic cancers was performed to evaluate the abscopal effect of radiotherapy on rectal cancer. Two different dual-tumor mouse models were established to investigate the efficacy of single dose and dose-fractionated radiotherapy combined with anti-CD25 or anti-CTLA4 and anti-Programmed cell death 1 ligand 1 (anti-PD1) mAbs on the local tumor growth and liver metastasis. The univariate Cox regression analysis, one-way analysis of variance, Dunnett’s test, a mixed-effect linear model and Kaplan-Meier survival analysis were used to calculate p values.Results The proportion of Tregs in pre-nRT biopsies was negatively correlated with prognosis (p=0.007). The retrospective analysis showed that regressing liver metastases were infiltrated by CD8+ T cells. In contrast, stable/progressing metastases and synchronous extracolonic cancers were characterized by PD1+ T cells and Tregs infiltration. Animal experiment results demonstrated that the combination of radiotherapy and anti-CD25/CTLA4 mAb resulted in a significant increase in CD8+ T cells and CD8+/CD4+ ratio in primary and secondary tumors compared with the irradiation alone group (all p<0.05 or p<0.01). The combined treatment was able to decrease Tregs, PD1+CD8+ and PD1+CD4+ T cells (p<0.05), suppress locally irradiated and distal unirradiated tumor growth, and improve overall survival rate. Radiotherapy in conjunction with anti-CTLA4 reduced liver metastasis (p<0.05).Conclusions These data indicated that radiotherapy plus depletion of Tregs was able to improve the antitumor response and generate an abscopal effect. |
url |
https://jitc.bmj.com/content/8/2/e000826.full |
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doaj-512ed9f583c74c18aab324cd0728851a2021-07-13T15:01:54ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-07-018210.1136/jitc-2020-000826Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancerJin Gu0Dengbo Ji1Can Song2Yongheng Li3Jinhong Xia4Yanjing Wu5Jinying Jia6Xinxin Cui7Songmao Yu8Surgical Oncology, Peking University Shougang Hospital, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, ChinaSchool of Life Sciences, Tsinghua University, Beijing, ChinaDepartment of Radiation Oncology, Key laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, ChinaKey Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Radiation Oncology, Key laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, ChinaBackground Distant metastasis is the major cause of mortality in patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy. Local radiotherapy can trigger an abscopal response to metastatic tumor cells. However, the abscopal effect is a rare event. CD4+ regulatory T (Treg) cell is a highly immune-suppressive subset which impedes immune surveillance against cancer, prevents the development of effective antitumor immunity and promotes tumor progression. We assume that the exploitation of the proimmunogenic effects of radiotherapy with anti-CD25 or anti-Cytotoxic T-Lymphocyte Associated Protein 4 (anti-CTLA4) monoclonal antibodies (mAbs) may enhance the local and abscopal effects in rectal cancer and improve the therapeutic outcome.Methods mRNA expression profiling of 81 pretreatment biopsy samples from LARC patients who received neoadjuvant radiotherapy (nRT) was performed to analyze the correlation between gene expression and prognosis. A retrospective analysis of patients with rectal cancer with distant metastasis or synchronous extracolonic cancers was performed to evaluate the abscopal effect of radiotherapy on rectal cancer. Two different dual-tumor mouse models were established to investigate the efficacy of single dose and dose-fractionated radiotherapy combined with anti-CD25 or anti-CTLA4 and anti-Programmed cell death 1 ligand 1 (anti-PD1) mAbs on the local tumor growth and liver metastasis. The univariate Cox regression analysis, one-way analysis of variance, Dunnett’s test, a mixed-effect linear model and Kaplan-Meier survival analysis were used to calculate p values.Results The proportion of Tregs in pre-nRT biopsies was negatively correlated with prognosis (p=0.007). The retrospective analysis showed that regressing liver metastases were infiltrated by CD8+ T cells. In contrast, stable/progressing metastases and synchronous extracolonic cancers were characterized by PD1+ T cells and Tregs infiltration. Animal experiment results demonstrated that the combination of radiotherapy and anti-CD25/CTLA4 mAb resulted in a significant increase in CD8+ T cells and CD8+/CD4+ ratio in primary and secondary tumors compared with the irradiation alone group (all p<0.05 or p<0.01). The combined treatment was able to decrease Tregs, PD1+CD8+ and PD1+CD4+ T cells (p<0.05), suppress locally irradiated and distal unirradiated tumor growth, and improve overall survival rate. Radiotherapy in conjunction with anti-CTLA4 reduced liver metastasis (p<0.05).Conclusions These data indicated that radiotherapy plus depletion of Tregs was able to improve the antitumor response and generate an abscopal effect.https://jitc.bmj.com/content/8/2/e000826.full |