Shaping Tumor Microenvironment by Amplifying the Complement Cascade for Improved Immune Response in Pancreatic Cancer Model

Antibodies against galactose-α-1,3-galactose (αGal) are among the most abundant natural antibodies in humans and have been exploited in cancer immunotherapy, with their efficacy partly attributed to complement activation. We aim to enhance this response by employing properdin [also known as factor P (FP)], the only known positive complement regulator. We expressed a membrane-anchored properdin (mFP) on mouse and human pancreatic cancer cells and assessed its ability to enhance αGal-mediated complement activation. We showed here that ectopic expression of mFP on Panc02 cells increased the deposition level of C3 in vitro and induced more potent complement-dependent cytotoxicity in the presence of human complement source. In an immunized Ggta1 knockout mouse model, which has circulating anti-αGal antibodies as a mimicry of the human system, mFP expression conferred significantly delayed tumor growth and was associated with pronounced remodeling of the immune landscape in the tumor microenvironment (TME). Specifically, we observed a marked increase in conventional type 1 dendritic cells, a reduction in tumor-associated monocytes/macrophages with a shift toward a pro-inflammatory phenotype, and a transition of CD8+ T cells toward a progenitor-exhausted state. Reconfiguring the structure of mFP to create an artificial C3 convertase binding site and incorporating an intracellular oligomerization domain improved target cell killing and monocyte-mediated phagocytosis in a human whole-blood loop model. These findings suggest that amplifying complement activation can delay tumor growth and alter the TME in the context of a murine pancreatic cancer model. Furthermore, we have developed a novel membrane-bound oligomerized FP functional unit, which effectively elicits robust complement activation.