Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer

Abstract

BackgroundDistant 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.MethodsmRNA 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.ResultsThe 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).ConclusionsThese data indicated that radiotherapy plus depletion of Tregs was able to improve the antitumor response and generate an abscopal effect.

CTLA-4 in Regulatory T Cells for Cancer Immunotherapy

“…Ji et al 2020 [136] In vivo investigated effect of administration of 0.25 mg anti-CTLA-4 monoclonal antibody on the CD25+Foxp3+ population in spleens and tumor tissues.…”

“…Various studies show that consolidated or novel types of CTLA-4 therapies correlate with different expression levels of T reg cells. Ji et al showed that the treatment of mice with 0.25 mg anti-CTLA-4 monoclonal antibody correlated with a lower level of the CD25+Foxp3+ T reg cell population ( p < 0.05) [ 136 ]. Qu et al observed that anti-CTLA-4 monoclonal antibodies enhanced IL36-stimulated antitumor activity by depleting T regs in the tumor [ 137 ].…”

Immune Modulation Plus Tumor Ablation: Adjuvants and Antibodies to Prime and Boost Anti-Tumor Immunity In Situ

“…Data from a pilot study conducted in breast cancer patients that received cryoablation and anti-CTLA-4 mAb showed good tolerability and promising efficacy (92). In the line of relieving immunosuppression, Treg depletion using anti-CD25 mAb enhances the anti-tumor response after RT, RFA and cryoablation, indicated by the increased presence of IFNy producing T cells after combination therapy in case of the latter two (89,93,94). Currently various clinical trials are ongoing testing the potential of in situ ablation and checkpoint blockade in different solid malignancies.…”

Biological Therapy with Complementary and Alternative Medicine in Innocuous Integrative Oncology: A Case of Cervical Cancer

“…Although there are no approved anti-CTLA-4-Treg inhibitors for CaCx to date, the presence of Tregs in HPV-induced cancers including CaCx, suggests the use of monoclonal antibodies to act as check point inhibitors in CaCx, but this remains to be an area of research [ 99 , 100 ]. Ji et al investigated the combination of radiotherapy and suppression of Tregs in rectal cancer and observed that this dual approach enhanced the efficacy of therapy with inhibition of metastasis [ 101 ].…”