The Synergistic Anti-tumor Effect of Iodine-125 Low-dose-rate Brachytherapy and Anti-PD-1 Therapy on Lung Cancer in Mice
Abstract Background: Radiotherapy (RT) when combined with anti-PD-1 therapy has a significant effect, but RT fractionation and dose impact the effects of this combined therapy. Iodine-125 particle implantation (125I RPI) is a hyperfractionated low-dose-rate brachytherapy. Its impact on the tumor immune microenvironment and the efficacy of 125I RPI combined with anti-PD-1 therapy are unknown. In this study, we evaluated the effectiveness of 125I RPI combined with anti-PD-1 therapy and their impact on tumor immunity. Methods: A Lewis lung cancer (LLC) mouse model was established and radioactive iodine-125 particles were implanted into the tumors. Tumor tissues were obtained six and 12 days after particle implantation, and the expression of PD-1/PD-L1 was detected by flow cytometry. On day 0, LLC cells were injected subcutaneously into the right hindlimb (primary tumor) and left flank (secondary tumor) of mice. On day 10, the mice were randomly divided into PBS, α-PD-1, 125I RPI, and α-PD-1+125I RPI groups. On day 22, tumor tissues were extracted from the mice. The proportion of immune cell subsets in the tumor immune microenvironment was detected by flow cytometry, and the primary and secondary tumor volumes were monitored. Results: After 125I RPI, the expression of PD-L1 on tumor cells was upregulated (P < 0.0001), and the proportion of CD8+ PD-1+ T cells also increased (P = 0.0001). 125I RPI combined with anti-PD-1 therapy synergistically inhibited primary (P = 0.0139) and secondary (P = 0.0494) tumor growth. The flow cytometry results showed that the combination therapy could increase the proportion of CD8+ T cells (P = 0.0055) and decrease the proportion of T regulatory cells (P < 0.0227) in the tumor microenvironment. Survival analysis shows that the sequence of 125I RPI and α-PD-1 affects efficacy, and early initiation of 125I RPI is more beneficial. Conclusion: 125I RPI combined with anti-PD-1 therapy can significantly inhibit tumor growth and activate anti-tumor immunity, which present a promising approach for the treatment of cancer.
