3505 - Effects and Mechanisms of Radiation Combined with Immunological Pneumonitis on Lung Cancer Progression
Presenter(s)
W. Jiang1, D. R. Jiao2, X. M. Zhang3, L. W. Wang3, and L. H. Wang4; 1Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China, 2Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, China,, Shenzhen, China, 3Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People’ s Hospital, Shenzhen, Guangdong, China, Shenzhen, China, 4Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China, Shenzhen, China
Purpose/Objective(s):
Radiotherapy plus immune checkpoint inhibitors is central to modern lung cancer treatment. Although this combination improves antitumor efficacy, overlapping toxicities—especially pneumonitis—may intensify. The effects of radiation pneumonitis (RP), checkpoint inhibitor pneumonitis (CIP), and their combination (RCIP) on tumor progression remain unclear. This study investigated how RP, CIP, and RCIP influence lung cancer growth and metastasis, and explored the underlying mechanisms.
Materials/Methods: Mouse models of treatment-related pneumonitis and orthotopic lung cancer transplantation were established. We compared tumor growth and metastasis across Control, RP, CIP, and RCIP groups. Tumor cells isolated from different pneumonitis microenvironments were tested for oxidative stress resistance (ROS assays), apoptosis resistance, and metastatic potential (migration/invasion assays). Immunohistochemistry and immunofluorescence were used to assess neutrophil infiltration and polarization in the tumor microenvironment (TME). Single-cell RNA sequencing was performed to characterize TME remodeling and intercellular signaling.
Results: RCIP suppressed primary lung tumor growth but significantly increased liver metastasis. RP also inhibited primary tumor growth, with no significant effect on liver metastasis. Compared with Control, RP, and CIP groups, tumor cells from the RCIP microenvironment showed stronger oxidative stress tolerance (P<0.05), greater anti-apoptotic capacity (P<0.0001), and enhanced migration/invasion (P<0.05). RCIP markedly increased neutrophil infiltration in the TME (P<0.01) and promoted a protumor neutrophil phenotype (P<0.05). Single-cell analysis showed that RCIP reshaped tumor antioxidant programs and enriched C3/C4 tumor subpopulations linked to neutrophil extracellular trap (NET) formation. RCIP also remodeled the TME, increasing neutrophils, B cells, dendritic cells, and NK cells. Notably, terminal neutrophil subpopulations (C0, C3), associated with poor prognosis in lung adenocarcinoma, were expanded, with upregulation of NET-related genes. Cell–cell communication analysis identified a malignant positive-feedback circuit between tumor cells and neutrophils via CXCL1/CXCL2 chemokine signaling and the IL-1 axis, jointly promoting progression.
Conclusion: RCIP exerts a context-dependent dual effect, suppressing primary lung tumor growth while paradoxically accelerating liver metastasis. This may be driven by enhanced tumor adaptation to oxidative stress, TME remodeling, and protumor neutrophil–tumor crosstalk. These findings refine our understanding of the toxicity–efficacy balance in radio-immunotherapy and provide a rationale for risk stratification and mechanism-based combination interventions.