Unexpected roles for complement proteins in cancer


C1S, C4d and factor H proteins of the complement system activate the progression of certain cancers, Lubka Roumenina’s group shows in two papers published in Cancer Immunology Research in May.

Lubka Roumenina’s team shows that certain proteins of the complement system (a component of innate immunity) play a role in the progression of certain cancers of the kidney (clear cell renal cell carcinoma, ccRCC) and lung (adenocarcinoma) as well as in the prognosis of these cancers. These results suggest that the complement system could be a new therapeutic target for these cancers in particular. They were published in two articles in the same consecutive issue of Cancer Immunology Research.

Novel non-canonical functions of the complement proteins C1s and FH associated with canonical functions of complement cascade activation promote tumor growth.

The complement system is a group of 35 proteins that act in a cascade in the immune response to eliminate pathogens during infection. When a pathogen is detected by the complement system, its constituent proteins induce inflammation, opsonization (deposition of specific molecules on the cell for degradation) and cell lysis (destruction). These are the classical or “canonical” functions of complement.

In recent years, various studies have shown that complement has “non-canonical” functions via certain proteins that could play a role in tumor progression.

Lubka Roumenina’s team was interested in these non-canonical functions via two complement proteins: C1s, a protease that acts at the beginning of the cascade by cleaving other proteins to make them active in the immune process, and FH, a regulator of complement activity.

In particular, C1s acts by cleaving C4 (another complement protein), releasing a C4d fragment of this protein. Daugan, Revel and colleagues found that high levels of C4d in the plasma and tumor cells of patients with kidney cancer (clear cell renal cell carcinoma, ccRCC) are associated with a poor prognosis. An elevated level of C4d therefore appears to be a biomarker of poor prognosis for these tumors.

The researchers observed a protumoral effect associated with an unusual localization of FH in the lysosomes and C1s in the cytoplasm in patients with ccRCC and lung adenocarcinoma (ADC). They thus show for the first time an intracellular function of complement proteins, known to act normally in the extracellular space.

For both C1s and FH, the proteins appear to be overexpressed in the tumors.  The high expression of C1s in human tumors has been correlated with increased infiltration and exhaustion of T cells, which are no longer able to destroy tumor cells.

To better understand the action of C1s and FH in tumor cells, the researchers created lines in which the genes for these two proteins were inactivated, and in which these proteins are therefore absent.

Inhibition of C1s and FH in tumor cells in vitro altered the transcriptional program, decreased proliferation and increased cell death. The absence of these proteins thus appears to have an anti-tumor effect.

The mode of action of the two proteins appears to be different. Deletion of C1s rendered tumor cells capable of inducing T cell activation in a co-culture model, restoring their ability to destroy tumor cells. Inhibition of FH resulted in decreased proliferation, due to cell cycle arrest, and increased mortality. In addition, in the absence of FH, cell migration is reduced, probably due to altered morphology, which may reduce metastasis.

These effects seem to be specific to the tumor type considered as no changes were observed in endothelial cells (HUVECs) or squamous cells of lung cancer upon suppression of FH expression. 

Therefore, overexpression of C1s and FH by tumor cells appears to be a novel escape mechanism that promotes tumor progression, in synergy with the tumor-promoting role of complement already known for ccRCC and lung adenocarcinoma. With this knowledge of the mechanisms of action of complement proteins and the prognostic impact of their overexpression, the authors highlight the strong potential of therapy targeting the complement system in selected subgroups of cancer patients.

Article 1: Complement C1s and C4d as prognostic biomarkers in renal cancer: emergence of noncanonical functions of C1s.

Daugan et al, Cancer Immunology Research, May 2021

Article 2: Intracellular Factor H drives tumor progression independently of the complement cascade.Daugan et al, Cancer Immunology Research, May 2021

Team Inflammation, Complement and Cancer

These results were the subject of an article on the Inserm IdF website. Read the article (in French)