Ruthenium-BODIPY photodynamic therapy for induction of immunogenic cell death and anti-tumor immunity 4628

Description Solid tumors that have low T cell infiltration may benefit from therapies that prime anti-tumor immunity. We are developing photodynamic therapy (PDT) agents that induce immunogenic cell death (ICD), engage macrophages (Mφ), and stimulate adaptive anti-tumor immunity. PDT works by activating a prodrug with a light source, allowing spatiotemporal control to reduce systemic toxicity. Our screen of several ruthenium (Ru) PDT compounds identified Ru-BODIPY as a prodrug that can be activated by tissue-penetrating green light. In vitro treatment induced endoplasmic reticulum stress after Ru-BODIPY PDT, indicated by elevated ATF4 and CHOP. ICD was evidenced by cell surface calreticulin exposure and ATP release in treated cells. We next tested for anti-tumor immune activation in vivo by treating orthotopic 4T1 triple-negative mammary tumors with Ru-BODIPY PDT. After treatment, immunohistochemistry of tumor tissue showed increased CD86+ M1-like Mφ, while leaving total CD68+ Mφ and Arg1+ M2-like Mφ similar between groups. In an efficacy experiment, 2/8 mice eliminated tumors, demonstrating systemic antigen memory by protection from contralateral rechallenge and increased antigen-specific interferon gamma production by splenocyte ELISpot. Elevated intratumoral IL-12 transcription in the remaining 6/8 treated mice suggests increased M1-like Mφ function with Ru-BODIPY PDT. These results show Ru-BODIPY PDT may influence the tumor microenvironment to induce systemic anti-tumor immunity. Funding Sources Supported by NSF grant CHE2102508 and the Wayne State University Grants Boost program. The Wayne State Univeristy Micropcopy, Imaging, and Cytometry Reseources Core is supported by NIH Center Grants P30 CA22453 and R50 CA251068-01. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)