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.

With complements: C3 inhibition in the clinic

“…Extracellular complement is very well studied and comprises a complex network of more than 50 cell membrane‐located, intracellular, and extracellular proteins 7 . Many of these are synthesized as inactive precursors that circulate in serum and interstitial fluid and function to activate one another in a cascading manner following an initial activating event 8 .…”

“…Apart from PNH, there are many diseases where complement is suspected or known to play significant part in disease pathogenesis 7 . Discussing all of those is beyond the scope of this review, so here we will focus on a few examples of disease where complement inhibition is being actively explored in the clinic.…”

“…Two of the largest classes of such diseases are autoimmune diseases and cancer. C3 has been implicated as a biomarker in several cancers; 119 therefore, it is conceivable that it could be a therapeutic target, particularly where it might contribute to immune suppression in the local cancer microenvironment or directly modulate cancer cell survival and proliferation 7 . The C5a‐C5aR axis has already been implicated as protumorigenic in a seminal paper by Markiewski et al 120 This study showed for the first time that complement plays a significant role in supporting tumor growth, inhibiting CD8 + T cell responses through recruitment of myeloid‐derived suppressor cells, and thus opening the possibilities for therapeutic inhibition of the complement cascade in cancer.…”

“…The C5a‐C5aR axis has already been implicated as protumorigenic in a seminal paper by Markiewski et al 120 This study showed for the first time that complement plays a significant role in supporting tumor growth, inhibiting CD8 + T cell responses through recruitment of myeloid‐derived suppressor cells, and thus opening the possibilities for therapeutic inhibition of the complement cascade in cancer. Since then, a few additional studies have reported on evidence of complement's role in the pathogenesis and progression of certain cancers 7 . These preclinical data have inspired clinical testing of C5aR1 inhibition, with two clinical studies in patients with advanced solid tumors currently underway (TJ210001 antibody by I‐Mab Biopharma and IPH5401 from Innate Pharma).…”

“…These preclinical data have inspired clinical testing of C5aR1 inhibition, with two clinical studies in patients with advanced solid tumors currently underway (TJ210001 antibody by I‐Mab Biopharma and IPH5401 from Innate Pharma). Readers are referred to 7 for further details. Investigators are also planning to test pegcetacoplan in patients with breast and ovarian cancer.…”