OHSU researchers led by Lisa M. Coussens, Ph.D., have revealed a novel mechanism underlying how cancer cells co-opt complement proteins of the immune system to promote tumor growth. And the researchers showed that using a targeted drug to block a key complement signaling pathway can boost the effectiveness of chemotherapy in an animal model of squamous cell cancers.
Coussens is a Knight Cancer Institute associate director and chair of the Department of Cell, Developmental and Cancer Biology in the OHSU School of Medicine. She and co-authors published their discoveries in the journal Cancer Cell.
Image: Immune cells expressing C5a receptors (brown staining) infiltrate a human head & neck squamous carcinoma (green stained cells).The complement system is made up of a large number of proteins that work in concert to target and eliminate invading pathogens by directing acute inflammatory responses to help eradicate infected tissues. Emergent data in recent years has implicated complement-driven inflammatory responses as also aiding and abetting malignancy.
Using a transgenic mouse model, Coussens and colleagues reported that macrophages, one of many immune cell types, direct the release of the complement protein C5a during premalignant progression, analogous to early wound or infection responses. In pre-malignant tissues, however, C5a instead regulates tumor-promoting properties of C5a-responsive immune cells, including suppression of T lymphocytes that normally kill cancer cells.
The findings are in contrast to recent studies highlighting the cancer-promoting role of other complement proteins such as C3, which normally acts upstream of C5a in a signaling cascade. Coussens and co-authors report that C3 activation is not required for squamous cancer development, revealing that squamous cell cancers can evolve to extrinsically activate complement C5a via the fibrinolytic or coagulation systems, or both, to promote cancer-associated inflammation while simultaneously evading the immune system’s cancer-killing T cells.
Demonstrating relevance for human cancers, the researchers reported that squamous cell cancer patient biopsies contain large numbers of infiltrating immune cells expressing C5a receptors. A further analysis of overall survival data from squamous cell cancer patients revealed that lower C5a receptor expression in tumors correlated with longer survival.
Therapeutically blocking C5a receptor signaling in their mouse model restored sensitivity to standard-of-care chemotherapy, thus indicating the potential of targeting C5a signaling as a new avenue for treating squamous carcinomas, which include cancers such as skin, esophagus, stomach, and prostate, among others.
Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy by Terry R.Medler, Dhaarini Murugan, Wesley Horton, Sushil Kumar, Tiziana Cotechini, Alexandra M.Forsyth, Patrick Leyshock, Justin J.Leitenberger, MollyKulesz-Martin, Adam A. Margolin, Zena Werb and Lisa M.Coussens. Cancer Cell (Oct. 8, 2018)