3142 - Targeting CD70 Enhances Radiosensitivity and Modulates Immune Microenvironment in Non-Small Cell Lung Cancer
Presenter(s)
C. Tian1,2, F. Wang2, S. Bao2, J. Ma2, H. Yang2, J. Liu2, J. Wang2, Y. Wang, M. Wu4, J. Yu4,5, and D. Chen2,6; 1Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 2Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 3Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 4Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 5Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
Purpose/Objective(s):
The upregulation of immunosuppressive molecules in tumor cells is one of the critical factors contributing to the development of therapeutic resistance. CD70, a tumor necrosis factor (TNF) superfamily member, has shown preclinical efficacy in overcoming EGFR-TKI resistance in non-small cell lung cancer (NSCLC), while anti-CD70 antibodies and CAR-T therapies are under Phase I/II trials for renal cell carcinoma and hematologic malignancies. However, the role of CD70 in radiotherapy remains unexplored. This study investigated CD70 as a prognostic biomarker for radiotherapy patients and explored its mechanism in radioresistance and immune microenvironment remodeling in NSCLC.Materials/Methods:
Transcriptomics and proteomics were employed to identify immunosuppressive molecules elevated in tumor cells following radiotherapy. Single-cell RNA sequencing (scRNA-seq) was used to explore gene expression changes in immune cells after radiotherapy. Spatial transcriptomics data were used to validate the correlation between CD70 expression and prognosis in NSCLC patients undergoing radiotherapy. Colony Formation Assay and subcutaneous tumor xenograft models were employed to verify the effects of targeting CD70 on radiosensitivity of NSCLC both in vitro and in vivo. Flow cytometry was used to assess the infiltration and the function of immune cells. Co-culture experiments between tumor cells and CD8+ T cells were conducted to validate the direct effects of tumor cells on CD8+ T cells.Results:
CD70 expression was increased post-radiotherapy and in radioresistant tumor cells. scRNA-seq and flow cytometry revealed concurrent upregulation of CD27 (the receptor of CD70) in CD8+ T cells after irradiation. Spatial transcriptomics revealed that high CD70 expression was related to shorter progression-free survival (PFS) in NSCLC patients with radiotherapy. CD70 overexpression reduced radiotherapy sensitivity in vivo, while in vitro assays showed no direct effect on radiosensitivity, suggesting an immune-dependent mechanism. CD70-overexpressing tumors exhibited diminished CD8+ T cell infiltration, impaired IFN-? production and elevated exhaustion markers. Conversely, CD70 knockdown or anti-CD70 antibody treatment restored tumor radiosensitivity and reversed CD8+ T cell dysfunction.Conclusion:
This study identifies CD70 as a novel prognostic biomarker and therapeutic target in NSCLC patients with radiotherapy. Radiation-induced CD70 elevation promotes CD8+ T cell exhaustion and impairs antitumor immunity. Targeting CD70 via genetic or pharmacological strategies overcomes radioresistance by restoring CD8+ T cell function and remodeling the immunosuppressive microenvironment. These findings provide a rationale for integrating CD70-targeted therapies with radiotherapy to improve outcomes in NSCLC patients.