Role of Complement Anaphylatoxins (C3a and C5a) in Lymphoma: A Systematic Review

Tumor cell survival, growth, and proliferation are related to the interactions between tumor cells and immune cells. Anaphylatoxins C3a and C5a seem to be involved in these cell-to-cell interactions. The aim of this study is to investigate whether the increase of C3a and/or C5a levels induces the proliferation of lymphoma cells. The population consisted of naïve lymphoma patients or human lymphoma cell lines. Comparisons of C3a and C5a levels between lymphoma patients and a healthy control group and between lymphoma cell lines and control media were acceptable. Studies that demonstrated outcomes regarding patients' survival and the growth and proliferation of lymphoma cells were included. A search was conducted on MEDLINE (through PubMed), Cochrane, and Scopus on January 2, 2025. Two independent reviewers performed the quality assessment using the Oral Health Assessment Tool (OHAT) modified for in vitro studies. Results were descriptively presented. Through a search of the aforementioned libraries, 852 studies were identified. Four studies were eligible: two studies used only cell lines, one used a cell line and paraffin blocks from 58 patients, and the other used serum from 39 naïve B-cell lymphoma patients. Regarding in vitro studies, it was shown that C5a induced neutrophil-mediated antibody-dependent tumor cell lysis. Elevated levels of C5a in co-culture with M2 macrophages lead to increased lymphoma cell proliferation, and patients with high densities of M2 macrophages in the tumor microenvironment (TME) had poor prognosis. Regarding the limitations of this review, only a few articles were found to study this hypothesis. Evidence of a correlation between anaphylatoxin levels and lymphoma cell proliferation raises the need for further investigation in order to understand the role of complement in B-cell lymphoma development and progression. In summary, anaphylatoxins, especially C5a, appear to play a role in the activation of lymphoma cells both as mediators in cell-cell interaction and as auxiliary molecules for the lysis of these cells via antibody-dependent cellular cytotoxicity.