2415 - Low-Dose Radiotherapy Enhances the Antitumor Immunity of ISABR in Non-Small Cell Lung Cancer
Presenter(s)
Z. Li1, and D. Qian2; 1Department of Radiation Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Hefei, China, 2Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
Purpose/Objective(s): Immunotherapy combined with stereotactic ablative radiotherapy (ISABR) has demonstrated promising efficacy in clinical settings. Low-dose radiotherapy (LDRT) can remodel the tumor immune microenvironment (TIME) and together with immunotherapy induces stimulation of anti-tumor immunity. Our study aims to investigate the effects of LDRT to ISABR and to provide new insights for clinical treatment strategies.
Materials/Methods: We established LLC-OVA lung cancer cells in C57BL/6J mice bearing unilaterally tumor (mimic primary lesion) and whole lung metastic tumor (mimic metastic lesions). The primary lesion were irradiated with SABR (8Gy × 3 fractions), and metastic lesions were irradiated with LDRT (1Gy × 3 fractions to whole lung) with systemic anti-PD1 administration. The mice were monitored for tumor growth and survival. Both peripheral blood and tumor species were analyzed using single-cell sequencing and validated by luminex multifactor assay, immunofluorescence staining and flow cytometry. Specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect.
Results: Comparing to ISABR, LDRT combined with ISABR significantly induced tumor regression, rendering tumors more vulnerable to immunotherapy. The combinatorial therapy exhibited superior antitumor efficacy mediated by cyto-CD8+ T cells and NK cells in preclinical NSCLC models. Treatment efficacy depended on the upregulation of NKG2D on NK cells, which enhanced their effector function and cytolytic capacity. Additionally, LDRT sensitized ISABR by recruiting cyto-CD8+ T cells into the primary lesion through the upregulation of CCR5- and CXCR3-related chemokines.
Conclusion: Our study demonstrates that LDRT targeting metastatic sites significantly enhanced tumor response to ISABR. These results further support the rationale for combining LDRT with ISABR and their clinical translation.