The role of complement in pancreatic cancer: from complement activation triggering and effector mechanism/s to combination with therapy

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis. Although the complement system has long been considered a component of immune surveillance, accumulating evidence indicates its pro-tumoral role in several cancer types. In this thesis, we explored the contribution of complement activation to PDAC progression using preclinical pancreatic tumor models and animals deficient for C3-upstream (C1q-/-, C4-/-, MBL1/2-/-, fB-/-) and -downstream (C3aR-/-, C5aR1-/-) molecules. Our results demonstrate that lectin pathway activation promotes tumor growth, partly through recognition of altered tumor cell glycosylation, as supported by in vitro N-glycosylation inhibition assays. Moreover, microbiome and mycobiome depletion experiments in vivo revealed that fungal components act as critical triggers of complement activation. Immune cell profiling showed that MBL1/2-/- and C4-/- tumors were enriched in NK and CD8⁺ T cells, and specific depletion experiments confirmed the pivotal role of CD8⁺ T cells in tumor control. To investigate downstream mechanisms, we employed C3aR-/- and C5aR1-/- mice, but observed no impact on tumor growth, prompting us to examine tumor-intrinsic pathways. Using CRISPR/Cas9, we selectively ablated C3aR in Panc02 cells, since it has been reported that complement receptors expressed by tumor cells may contribute to migration, invasiveness, and therapy resistance. Finally, combining MBL1/2 deficiency with radiotherapy we observed a synergistic effect in controlling tumor growth. Collectively, these findings identify lectin pathway activation, altered tumor cell glycocalyx and fungal triggers, and tumor-intrinsic complement as key drivers of PDAC progression, and suggest that complement targeting may enhance the efficacy of established therapies.