2504 - Synergistic Anti-Tumor Immune Response of In Vitro Irradiated Cancer Vaccine with PD-1 Blockade and Radiotherapy in a Humanized Mouse Model
Presenter(s)
S. W. Hong1, S. Kim2, Y. Kim2, N. Park2, S. H. Jeon3, and I. A. Kim4; 1Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea, Republic of (South), 2Department of Tumor Biology, Seoul National University Graduate School of Medicine, Seoul, Korea, Republic of (South), 3Seoul National University Bundang Hospital, Seongnam, Korea, Republic of (South), 4Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea, Republic of (South)
Purpose/Objective(s): Syngeneic murine model demonstrated that in vitro–irradiated cancer vaccine (ICV) elicits anti-tumor responses. However, given the substantial differences between murine and human immune systems, validation in a human-relevant system is required for clinical translation. This study utilizes a humanized breast cancer mouse model to provide a comprehensive view on the transcriptomic and immunological changes following ICV and its combination with local radiotherapy (RT) and aPD-1 blockade.
Materials/Methods: Humanized NSG mice engrafted with human CD34+ hematopoietic stem cells were inoculated with MDA-MB-231 triple-negative breast cancer cells. Mice were treated with ICV, RT, and aPD-1 (pembrolizumab). Therapeutic efficacy was evaluated by monitoring primary and secondary tumor growth. Additionally, the underlying immunologic responses were investigated using bulk RNA-sequencing, flow cytometry, and gut microbiome profiling.
Results: ICV monotherapy significantly delayed tumor growth and induced transcriptomic shifts similar to local RT, including T-cell activation and type II interferon responses. Triple combination therapy (TCT) demonstrated anti-tumor synergy at both primary and distant sites. TCT resulted in the increased infiltration and proliferation of CD8+ T cells, as well as splenic effector memory cells without increasing regulatory T cells (Tregs). Furthermore, TCT triggered a shift in the tumor microenvironment toward an antigen-presenting cancer-associated fibroblast (apCAF) phenotype, characterized by MHC-II (CD74, HLA-DRA) upregulation. Longitudinal microbiome analysis identified a treatment-specific enrichment of the immunomodulatory commensal Lactobacillus within TCT group.
Conclusion: The integration of transcriptomic and immunological analyses in a humanized mouse model validated that ICV is an effective anti-tumor strategy that complements RT and aPD-1. By overcoming the limitations of syngeneic models, this study provides a mechanistic framework for the clinical translation of ICV as a component of multi-modal immunotherapy (Work supported by the grants from Korea Hydro & Nuclear Power Co.,Ltd.# 2024-TECH-18; I.A. Kim).