The Role of the Complement in Clear Cell Renal Carcinoma (ccRCC)-What Future Prospects Are There for Its Use in Clinical Practice?

Abstract

In recent years, the first-line available therapeutic options for metastatic renal cell carcinoma (mRCC) have radically changed with the introduction into clinical practice of new immune checkpoint inhibitor (ICI)-based combinations. Many efforts are focusing on identifying novel prognostic and predictive markers in this setting. The complement system (CS) plays a central role in promoting the growth and progression of mRCC. In particular, mRCC has been defined as an "aggressive complement tumor", which encompasses a group of malignancies with poor prognosie and highly expressed complement components. Several preclinical and retrospective studies have demonstrated the negative prognostic role of the complement in mRCC; however, there is little evidence on its possible role as a predictor of the response to ICIs. The purpose of this review is to explore more deeply the physio-pathological role of the complement in the development of RCC and its possible future use in clinical practice as a prognostic and predictive factor.

Keywords: biomarkers; classical pathway; complement; immunotherapy; mRCC; “aggressive complement” tumor.

Figure 1

Canonical pathways of the complement activation and interaction of the coagulation system with the CS. Abbreviations. C1 INH, C1 inhibitor; DAF, decay-accelerating factor, or CD55, cluster of differentiation 55; C4BP, C4, binding protein; MCP, membrane cofactor protein, or CD46, cluster of differentiation 46; FH, factor H; FD, factor D; FI, factor I; MAC, membrane attack complex.

Figure 2

Local complement activation: the fundamental role of “complosome”. (A) T-cell-expressed protease cathepsin L (CTSL) processes C3 into biologically active C3a and C3b. “Tonic” intracellular C3a generation is required for homeostatic T cell survival through mTOR activation. This intracellular CS is defined as “complosome”. (B) As a result of T cell activation, the activated intracellular complement and complement receptors are secreted by T cells; C3a and C3b bind to C3aR and CD46 (membrane cofactor protein, MCP), respectively, and promote protective T Helper1 (Th1) differentiation. The activation of T cell receptors (TCRs) promotes also intracellular C3, C5, FH, FD secretion. Moreover, intracellular C5 activation (induced by CD46) and stimulation of C5a receptor 1 (C5aR1) promote pyrin-domain-containing protein 3 (NLRP3) inflammasome assembly, caspase-1-dependent interleukin-1β secretion, and induction of Th1 functional activation. In the early stages, CD46 promotes differentiation and expansion of T cells into Th1 effector lymphocytes. However, in the second phase, CD46, in association with the IL-2 receptor (IL-2R), leads to a Th1 restriction, promoting the secretion of IL-10. This is associated with the expression of C5aR2 via surface-shuttled C5a/C5a-desArg, which probably has a role in assisting this inhibitory signal. In addition, a synergistic effect has been observed between Toll-like receptor (TLR) and complement receptors expressed on the antigen-presenting cells (APCs). Abbreviations. APC, antigen-presenting cells; CTSL, T-cell-expressed protease cathepsin L; MHC II, major histocompatibility complex class II; TLR, Toll-like receptor; C3aR, C3a receptor; C5aR, C5a receptor; IL-2R, interleukin-2 receptor; NLRP3, NLR family pyrin-domain-containing 3.

Figure 3

Activation of the CS in an RCC microenvironment. The first step is represented by C1q TAM secretion that contributes to pro-tumoral TAM phenotypes, T cell exhaustion, adhesion of tumor cells to the extracellular matrix, and neoangiogenesis. RCC cancer cells produce C1r and C1s, leading to an active C1 complex formation. This, in association with IgG deposits on tumor cells, promotes the classical pathway of the CS. Tumor cells also secrete the subsequent complement components, leading to C4 and C3 activation fragment deposition (C4b, C4d and C3b, iC3b, C3d). Moreover, anaphylatoxins C3a and C5a produced by the activation of the classical pathway modulate tumor cells and TME. Abbreviations: TAMs, tumor-associated macrophages; mDCs, myeloid dendritic cells.