Y. Xuan, R. Wu, Y. WANG, L. Xu, X. Jin, Y. Deng, and Z. Zhang; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
Purpose/Objective(s): In recent years, studies have indicated that the combination of radiotherapy and immunotherapy can effectively enhance the complete response rate in locally advanced rectal cancer. However, there is a lack of research specifically addressing the use of radiotherapy combined with immunotherapy in elderly rectal cancer patients. Aging may induce cellular and molecular changes in the tumor microenvironment, impacting tumor development and treatment responses. This study aims to explore the impact of aging on the combination of radiotherapy and immunotherapy in a mouse model. Materials/
Methods: The CT26 cell line was used to construct subcutaneous tumor-bearing models in both young mice (6-8 weeks old) and elderly mice (>11 months old). The mice were treated with PD-1 monoclonal antibody, CTLA-4 monoclonal antibody, radiotherapy alone, radiotherapy combined with PD-1 monoclonal antibody, radiotherapy combined with CTLA-4 monoclonal antibody, and saline as a control. "Relative change in tumor volumes" was used to compare tumor control in the same treatment groups between young and elderly mice. Ly6G monoclonal antibody was used to deplete neutrophils in elderly mice receiving radiotherapy and PD-1 monoclonal antibody treatment. Tumor growth was monitored, and differences in tumor microenvironment were explored through flow cytometry. Results: Tumor growth in elderly mice was significantly faster than in young mice after cell inoculation. In the groups of young mice receiving radiotherapy combined with PD-1 or CTLA-4 monoclonal antibody, 57.1% and 71.4% achieved complete response, respectively. However, the tumor control and survival benefits of PD-1/CTLA-4 monoclonal antibody treatment, radiotherapy, and combined treatment were less pronounced in elderly mice compared to the same treatment groups in young mice. Flow cytometry results showed that the proportions of DCs, M1 macrophages, CD8+ effector T cells, and CD4+ effector T cells in the tumor microenvironment of elderly mice were significantly lower. In contrast, M2 macrophages, Ly6G+ cells, and Treg cells were significantly higher. Compared with mice that only received radiotherapy and PD-1 treatment, elderly mice receiving Ly6G antibody ahead showed significantly improved tumor control, a significant reduction of M2 macrophages, and a significant increase of NK cells. Conclusion: Compared to young mice, tumors grew faster in elderly mice, and the tumor control of all treatments above was less effective in elderly mice. In the tumor microenvironment of elderly mice, there were higher levels of immunosuppressive cell infiltration. Aging modulates neutrophil-mediated immunotherapy resistance in mouse models of rectal cancer, and neutrophil depletion was able to relieve the resistance.
