2080 - Irradiated Tumor Cell-Released Microparticles and the Therapeutic Efficacy of PD-1 Inhibitors by Promoting M1-TAMs Polarization in NSCLC Brain Metastases

J. Li¹, M. Bai², W. Jia³, X. Zhai⁴, and H. Zhu⁵; ¹Department of Radiation Oncology, Shandong Cancer Hospital & Institute Affiliated to Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Jinan, China, ²2.Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China., Jinan, Shandong, China, ³Department of Radiation Oncology, Shandong Cancer Hospital & Institute Affiliated to Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Jinan, Shandong, China, ⁴Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China, ⁵Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

Purpose/Objective(s): Brain metastases (BMs) are the most common site of metastasis in patients with non-small cell lung cancer. Due to the presence of the blood-brain barrier, BMs have poor response to immunotherapy and present an immunosuppressive microenvironment. In this study, we focus on radiation-induced vesicles secreted by tumor cells (RT-MPs) that have the ability to cross the blood-brain barrier and influence the intracranial immune microenvironment. It is expected to provide a new treatment plan for the NSCLC patients with brain metastases Materials/

Methods: We use intra-carotid artery injection and orthotopic injection to establish animal models of BMs, observe the effects of RT-MPs on the number and role of CD4⁺ T cells,CD8⁺ T cells, TAMs and other immune cells in BMs, detect the effects of Arg1, IL12, INOS and other cytokines, and the effects of brain metastases on immunosuppressive responses. Single cell sequencing technology was used to identify the cell subsets and signaling pathways of RT-MPs.
Results: By using animal models of BMs, we observed that RT-MPs can penetrate the blood-brain barrier and be swallowed by TAMs. Then shift the microenvironment TAMs from M2 phenotype to M1 phenotype, thereby modulating the interactions between TAMs and tumor cells. Analysis through single-cell sequencing demonstrated that TAMs, after internalizing RT-MPs, chemokine signaling pathways are activated, secreted more chemokines, such as CCL5, CXCL2, CXCL1, CCL3, CCL4, and CCL22, attracting more CD4⁺ T cells and CD8⁺ T cells, improving immune-mediated killing, and enhancing subsequent combination anti-PD-1 therapy. These findings provide a preclinical foundation for exploring alternative treatments for patients with immunoresistant NSCLC brain metastases.
Conclusion: Irradiated tumor cell-released microparticles can reshape the immune microenvironment of brain metastases and enhance the therapeutic efficacy of PD-1 Inhibitors by promoting M1-TAMs polarization in NSCLC brain metastases.