– COMPACT

Malignant cells are supported by their interaction with the tumor microenvironment (TME). This is orchestrated by the host cells and by soluble mediators, including the components of the complement system. Complement is a key player in immune defense against pathogens and in the maintenance of cell homeostasis. In cancer, the final impact of the complement is, therefore, the sum of two opposing forces: 1) The anti-tumor opsonophagocytosis and cytotoxicity and 2) the pro-tumor chronic inflammation mediated by C5a/C5aR1 axis, which impairs antitumor T cell responses.
We have previously reported that the co-regulated overexpression of key complement genes correlates with poor prognosis in a subset of cancers (complement aggressive group) and with favorable outcome in another subset (complement protective group). Despite these clear-cut gene expression correlations, the knowledge gap on the mechanisms of this context-dependent role of complement in cancer has not been bridged, hampering the identification of reliable biomarkers for stratifying patients who may respond to different types of complement-targeting therapy alone or in combination with other anticancer agents.
Having demonstrated that “one size does not fit all”, our COMPACT project addresses the challenge of understanding complement activation in cancer by tackling the following aims: 1) to elucidate the role of the innate immune complement system as a therapeutic target in cancer by creating a comprehensive atlas of complement activation patterns in lung cancer (both adenocarcinoma and squamous cell carcinoma) and head and neck squamous cell carcinoma, two cancer types in which complement seems to be activated by distinct mechanisms, 2) to test treatment strategies in pre-clinical human models of these cancer types, and 3) to identify companion biomarkers to stratify patients for inclusion in a future clinical trial for complement targeting in cancer patients.