Immune profiling of radiation-immunotherapy synergy in an autochthonous breast cancer model 4116

Description Anti-PD1 (aPD1) immunotherapy combined with chemotherapy has shown promise in triple-negative breast cancer (TNBC), yet high toxicity and therapeutic resistance are significant challenges that warrant exploration of alternative treatment strategies. Using a genetically engineered autochthonous Myc-p53 TNBC mouse model, we investigated the potential synergy of targeted radiotherapy (RT) and aPD1 immunotherapy in a manner that recapitulates the ongoing Pembrolizumab-Radiation (P-RAD) clinical trial (NCT04443348). Tumor-bearing mice were randomized into 4 groups (n = 10/group): IgG isotype control, aPD1, RT/IgG, or RT/aPD1. RT (24Gy) was delivered over 3 days, and aPD1 (10mg/kg) was administered twice weekly. RT/aPD1 significantly reduced tumor volume compared to IgG and aPD1 alone, which was confirmed histopathologically. Tumors were analyzed on day 23 by high parameter spectral flow cytometry. Compared to IgG, RT/aPD1 treated tumors had increased CD11c+MHCII+CD69+ activated dendritic cells (DCs), CD11b+F4/80+MHCII+ activated macrophages, CD19+ B cells, and recently activated CD4+ and CD8+ T effector cells. Ongoing analysis of bulk RNAseq data will explore gene signatures and pathways involved. Thus, our preclinical autochthonous TNBC model demonstrates synergy between aPD1 with localized RT that is associated with activation of professional antigen presenting cells and effector B and T lymphocytes. Future work will explore candidate mechanisms of response and resistance. Funding Sources Supported by Merck OTSP #101113; Dept of Defense HT94252310961; NCI R01 CA274254; NCI SPORE P50 CA058223 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)