Abstract B006: Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy
Authors: Guglietta Silvia , Weber Lukas M. , Fosso Bruno , Marzano Marinella , Hardiman Gary , Olcina Monica , Robinson Mark D. , Krieg Carste 
Published: December 2022

Abstract
Background: The role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC as inflammation can enhance response to immune checkpoint blockade (ICB) therapy. Yet, the majority of CRC are poorly infiltrated and even in presence of an inflammatory infiltrate half of these cancers become refractory to ICB. Therefore, there is a need to identify mechanisms to establish therapy supportive inflammation. We have previously reported that, irrespective of their MSI-H or MSS status, about 10% of patients with CRC down-regulate the receptor for the complement anaphylatoxin C3a (C3aR) via methylation-dependent mechanisms. The complement system is a well characterized first line of defense against pathogens and a central component of the immune response. Emerging evidence suggests that complement C3aR may play a role in intestinal homeostasis. However, to date, it is unknown how the C3a/C3aR axis can affect CRC development and influence response to therapy with ICB. Methods: We used here a comprehensive approach encompassing analysis of publicly available human CRC human datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multi-platform high dimensional analysis of immune responses and microbiota sequencing, RNASeq and mass cytometry. Results: Using our novel mouse model of CRC (APCMin/+/C3aR-/-) we showed that loss of C3aR resulted in enhanced immune infiltration in typically “cold” tumors and changes in the intestinal microbiota. Similarly, we found that down-regulation of the complement C3aR in patients correlates with changes in specific tumor-infiltrating immune cells. Notably, when treated with a-PD1, APCMin/+/C3aR-/- mice showed a significant reduction in their tumor multiplicity and tumor load compared to untreated mice, suggesting that the loss of C3aR unleashes in the colon a microbiota-mediated favorable inflammatory infiltrate that can be exploited by the immunotherapy to reduce both de novo tumor development and the growth of already existing tumors. Conclusions: Our findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. Our results suggest that C3aR may be exploited to overcome ICB resistance in a larger group of CRC patients.
Citation Format: Silvia Guglietta, Lukas M. Weber, Bruno Fosso, Marinella Marzano, Gary Hardiman, Monica Olcina, Mark D. Robinson, Carste Krieg. Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B006.