Opposing Roles for Complement Component C5a in Tumor Progression and the Tumor Microenvironment

Abstract

Promoting Complement (C) activation may enhance immunological mechanisms of anti-tumor antibodies for tumor destruction. However, C activation components, such as C5a, trigger inflammation which can promote tumor growth. We addressed the role of C5a on tumor growth by transfecting both human carcinoma and murine lymphoma with mouse C5a. In vitro growth kinetics of C5a, control vector (CV), or parental cells revealed no significant differences. Tumor-bearing mice with C5a-transfected xenografted tumor cells had significantly less tumor burden as compared to CV tumors. NK cells and macrophages infiltrated C5a expressing tumors with significantly greater frequency while VEGF, arginase, and TNF-α production were significantly less. Tumor-bearing mice with high C5a-producing syngeneic lymphoma cells had significantly accelerated tumor progression with more Gr-1+CD11b+ myeloid cells in spleen and overall decreased CD4+ and CD8+ T cells in tumor, tumor-draining lymph nodes (TDLN), and spleen. In contrast, tumor-bearing mice with low C5a-producing lymphoma cells had a significantly reduced tumor burden with increased IFN-γ-producing CD4+ and CD8+ T cells in spleen and TDLN. These studies suggest concentration of local C5a within the tumor microenvironment is critical in determining its role in tumor progression.

A Complement-Optimized EGFR Antibody Improves Cytotoxic Functions of Polymorphonuclear Cells against Tumor Cells

“…These findings supported the EhlenbergerNussenzweig hypothesis that complement binding to complement receptors is crucial to increase IgG presentation to phagocyte Fc receptors such as FcgRIIIb, thereby increasing IgG-mediated effector functions against pathogens (40). Although it has been demonstrated in mouse models that C5a promotes activation and recruitment of neutrophils to sites of viral (41), bacterial, or fungal (42) infections, opposing roles of C5a in tumor progression have been described (43). Notably, tumorbearing mice with C5a-transfected in comparison with control vector-transfected xenografted tumors displayed lower tumor burden.…”

“…Notably, tumorbearing mice with C5a-transfected in comparison with control vector-transfected xenografted tumors displayed lower tumor burden. In contrast, tumor-bearing mice with high C5a-producing in comparison with low C5a-producing syngeneic lymphomas showed higher myeloid cell accumulation in the spleen and accelerated tumor progression (43). In line with these findings, tumor growth-promoting activities of complement activation, especially by the C5a signaling cascade, have been described as being evoked by augmented tumor infiltration of myeloid-derived suppressor cells, leading to the suppression of antitumoral T cell responses (44).…”

The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses

“…Complement is now thought to be a key component of cancer-related inflammation, and a recent study has suggested that exacerbated inflammation in the tumor microenvironment promotes genetic instability (25). The canonical proinflammatory mediator C5a has been widely implicated for a role in tumor growth, with both tumor-promoting and tumor-inhibitory effects reported, depending on tumor type, immune status of the host, and C5a levels (6)(7)(8)(9)26). Although these and other studies (27) have shown that tumor growth is reduced in the absence of C3 (which generates both C3a and C5a), the tumor-promoting effects have been attributed solely to C5a.…”

Le système du complément

“…Cependant, cet effet immunomodulateur des anaphylatoxines sur le microenvironnement immunitaire reste, encore une fois, controversé en fonction des données de la littérature, particulièrement selon le type de tumeur concerné et la concentration des anaphylatoxines. Dans différents modèles murins de sarcome du sein, de cancer de l'ovaire et de lymphome [34], l'expression par les cellules tumorales du C5a ralentit la croissance tumorale, en comparaison à celle observée chez des souris n'exprimant pas cette anaphylatoxine. Plusieurs hypothèses ont été émises afin d'expliquer cet effet anti-tumoral de la protéine.…”

“…Il pourrait aussi participer à l'élimination des cellules tumorales en attirant les macrophages et les granulocytes par chimiotactisme. Dans le modèle de lymphome, en particulier, la concentration locale de C5a aurait un effet direct sur la croissance tumorale [34] : les tumeurs sécrétant de fortes quantités de C5a voient leur croissance accélérée alors qu'une quantité moindre de la protéine lui confère des propriétés anti-tumorales. Dans ce modèle, les effets anti-tumoraux du C5a sont principalement liés à une augmentation de la production d'IFN- (interféron gamma) par les lymphocytes T CD4 et CD8 dans la rate et les ganglions.…”