Senior Researcher Stowers Institute for Medical Research Kansas City, Missouri, United States
Abstract: Targeting C5AR1 Signaling to Overcome Immune Exclusion and Enhance Immunotherapy in Colorectal Cancer
Xi He; Linheng Li Immunotherapy has shown limited efficacy in colorectal cancer (CRC) primarily due to the immune-excluded tumor phenotype. In this context, immune cells, particularly CD8+ T cells, tend to accumulate at the tumor periphery rather than infiltrating the tumor core. Our studies focus on cancer stem cells (CSCs) and their tumor microenvironment. We revealed that myeloid-derived suppressor cells (MDSCs) play a key role in immunosuppressive niche, which is in part mediated by the C5AR1 signaling module. Using the MC38 mouse colon cancer model, we treated mice with an C5AR1 inhibitor and resulted in about 40% reduction in tumor mass. To investigate tumor and the associate microenvironment, we take the following approaches including imaging, single-cell secretome analysis, scRNA-sequencing, and spatial transcriptomics. We found that inhibition of C5AR1 increased infiltration of immune cells including macrophages, CD8+ T cells, and NK cells to the core of tumors from the tumor periphery. Additionally, Single-cell secretome analysis using Isoplexis confirmed the downregulation of immunosuppressive signals (TGFβ, IL-10) and upregulation of inflammatory signals (TNFα, IFNγ). We further validated our finding using the organoid-transplanted colorectal cancer (CRC) model carrying Apc, Ras, and P53 mutations with Xenium spatial transcriptomics. This technology utilizes a probe-based hybridization method for precise spatial profiling. Intriguingly, Inhibition of C5AR1 converted the CRC from immune-excluded into immune-inflamed, thus enhancing CRC immune responses by disrupting the CSC-MDSC interaction
