Conventional Fractionated Elective Nodal Irradiation Preserves Early Antitumor Immunity and Efficacy Compared With Hypofractionated Protocols.

Abstract

Although clinical elective nodal irradiation (ENI) often uses conventional fractionation, most animal ENI studies employ hypofractionated protocols. This study evaluated the influence of ENI dose fractionation on tumor immunity and antitumor efficacy in murine models. Splenocytes were irradiated (≤20 Gy) to assess radiosensitivity and immune function. ENI was performed on MC38 and SCC7 tumor models, targeting inguinal lymph nodes with 3 schedules: no ENI (0 Gy), conventional fractionated ENI (Conv-ENI; 2 Gy × 8 fractions), and hypofractionated ENI (Hypo-ENI; 9.8 Gy × 1 fraction). Tumors received 2 Gy × 12 fractions. Antitumor effects, tumor-infiltrating lymphocytes, tumor-draining lymph nodes, and lymphocytes in blood were analyzed longitudinally. Lymphocyte trafficking was inhibited using FTY720 duringENI. Irradiation (≤3 Gy) reduced lymphocyte viability in a dose-dependent manner; however, it did not impair immune function, whereas 9.8 Gy reduced viability and impaired immune functions. Hypo-ENI showed inferior antitumor effects compared with Conv-ENI across tumor models, with the no-ENI group demonstrating effective antitumor control. In the MC38 model, CD8⁺tumor-infiltrating lymphocytes were significantly reduced in the Hypo-ENI group on day 1 but not in the Conv-ENI group. CD8⁺ lymphocytes in tumor-draining lymph nodes were unaffected across groups on day 1 but significantly reduced in the Hypo-ENI group after FTY720 administration. The number of lymphocytes in blood was significantly reduced in the Hypo-ENI group on day 1. The negative impact of conventional fractionated ENI on tumor immunity and antitumor efficacy may be less severe than previously assumed based on studies using hypofractionated protocols. Future studies should consider the possibility that conventional fractionated ENI and hypofractionated ENI may have different effects on the dynamics of lymphocyte trafficking and their antitumor immunity.