Z. Zhu1,2, X. Duan3, J. Y. Luo4, W. Wang5, X. Chen6, and Q. Peng7; 1Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China, 2Southwest Medical University, Luzhou, Sichuan, China, 3Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine University of Electronic Science and Technology of China, Chengdu, People’s, Chengdu, sichuan, China, 4Department of Colorectal Surgery, Sichuan Cancer Hospital &Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan, China, chengdu, sichuan, China, 5Department of Colorectal Surgery, Sichuan Cancer Hospital &Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan, China,, Chengdu, sichuan, China, 6West China Campus of Sichuan University, Wuhou District, Chengdu, Sichuan Province, China, chengdu, sichuan, China, 7Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, sichuan, China
Purpose/Objective(s): The combination of immunotherapy and radiation therapy (RT) has demonstrated potential therapeutic advantages in the treatment of colorectal cancer, yet survival has not been significantly prolonged in some colorectal cancer patients. Currently, enhancing tumor sensitivity to radiation therapy has become an important challenge in clinical treatment. The molecular mechanism of IL-12 as an anti-tumor and radiosensitizing cytokine is still unclear. In this study, we used DMP nanocarriers conjunction with IL-12 to improve the therapeutic efficacy by combining radiation therapy, aiming to elucidate the tumor-suppressing and radiosensitizing effects of DMP/IL-12 complexes in colorectal cancer and the preliminary molecular mechanisms. Materials/
Methods: First, we validated the inhibitory and radiosensitizing effects of DMP/IL-12+RT on colorectal cancer cell lines by a cell counting kit and cell clone formation assays. Subsequently, a mouse model of C26 colon cancer was established, and DMP nanogene carriers with targeted delivery of IL-12 cytokines were injected into the mouse tumor. The treatment regimen was DMP/IL-12 injection starting on the 7th day after loading the tumor for 7 consecutive days, and combined radiation therapy starting on the 13th day after loading the tumor at a daily dose of 2 Gy for 5 consecutive days. One week after the end of treatment, mouse tumors were taken and stained with hematoxylin-eosin (H&E) and immunohistochemical staining to observe the growth of tumor cells in different treatment groups. Flow cytometry was used to further detect DMP/IL-12+RT induced immune cell infiltration in tumor tissues. Results: The results of the study by pathological staining showed that the combination of DMP/IL-12+RT exhibited significant effects in improving tumor growth inhibition. Flow cytometry showed a significant increase in the infiltration and activation of natural killer cells, macrophage cells and T cells in the tumor tissues of mice treated with DMP/IL-12+RT. This effect was significantly observed not only in tumor tissues but also verified in the blood of mice. The secretion of MCH-II and IFN-? was correspondingly increased in the tumors of the co-treated mice, suggesting the formation of a pro-inflammatory tumor microenvironment. The results of this series of experiments not only verified the significant effect of DMP/IL-12+RT combination therapy at the cellular level, but also further confirmed its radiosensitizing effect through the prolongation of survival and inhibition of tumor growth in animal experiments in mice. Conclusion: We demonstrated that DMP/IL-12 combined RT treatment enhanced the effect of radiosensitization by modulating the tumor immune microenvironment, resulting in significant inhibition of tumor growth. DMP/IL-12 exhibits potential therapeutic capabilities as a radiosensitizer for colorectal cancer, and provides new ideas for optimizing comprehensive treatment of colorectal cancer.
