Inside-Out of Complement in Cancer

Abstract

The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal role of complement in fighting microbes, complement seems to suppress antitumor immunity via regulation of host cell in the tumor microenvironment. Although most studies link complement in cancer to complement activation in the extracellular space, the discovery of intracellular activation of complement, raises the question: what is the relevance of this process for malignancy? Intracellular activation is pivotal for the survival of immune cells. Therefore, complement can be important for tumor cell survival and growth regardless of the role in immunosuppression. On the other hand, because intracellular complement (the complosome) is indispensable for activation of T cells, these functions will be essential for priming antitumor T cell responses. Here, we review functions of complement in cancer with the consideration of extra and intracellular pathways of complement activation and spatial distribution of complement proteins in tumors and periphery and provide our take on potential significance of complement as biomarker and target for cancer therapy.

Keywords: biomarkers; cancer; complosome; extracellular complement; intracellular complement; therapy; tumor microenvironment.

Figure 1

Sites of complement expression and activation. Cartoon representing the main sources of complement in the tumor and their main modes of activation and action. C3 and factor H have shown to exert their function both intra- and extracellularly. Other proteins such as C5 were shown to have extracellular function via its receptors. Generally extracellular complement works by inducing immunosuppressive phenotype. Intracellular complement has the potential to modulate immune cell function in similar fashion or by directly increasing proliferation and migration capacity of the cancer cells themselves. In addition, lack of C3aR and C5aR signalling on T cells can convert them into Tregs which in turn can suppress other T cells’ function.

Figure 2

Examples of the effect of extracellular complement in different cancers. Schematic representation of published mechanisms describing different roles of complement proteins in different cancers.

Figure 3

Potential therapeutic intervention points. Complement proteins can be expressed and secreted by almost all cells in the tumor microenvironment, and in the lymph nodes and are present in serum. This cartoon outlines potential targets either intracellularly or extracellularly that could be either inhibited or activated in the case of the immune cells. It is possible that in the future complement inhibiting therapeutics should be able to act extracellularly to promote immune cell antitumor immunity. Reversely intracellular complement in immune cells can be promoted as it is expected to have antitumorigenic effect and promote inflammation. Discreet complement targets present in the tumor cells but not in the immune cells and vice versa would have to be discovered to obtain full clinical efficacy of complement targeting therapy.