The novel B-cell epitope peptide vaccine, MAX449, exhibits significant anti-tumor efficacy and enhances the therapeutic effects of PD-1 antibodies on tumors by modulating the activity of PMN-MDSCs.

Evidence accumulating across experimental studies and clinical settings supports a central role for the C5a-C5aR signaling axis in promoting tumor progression and immune evasion. Nevertheless, whether a vaccination approach targeting C5a can elicit robust anti-tumor immune responses and suppress tumor growth has not yet been investigated. This research aimed to develop an efficient B-cell peptide epitope vaccine targeting the C5a-C5aR pathway for cancer therapy. Chimeric C5a B-cell peptide epitope vaccines were synthesized using high-performance liquid chromatography (HPLC), and C5a antibodies titers were determined using enzyme-linked immunosorbent assay (ELISA). Multiple mouse tumor models were employed to evaluate the vaccine's efficacy. The mechanisms of MAX449 were assessed through in vitro and in vivo approaches, incorporating single-cell RNA sequencing (scRNA-seq), flow cytometry, western blotting, real-time quantitative PCR, transwell migration assays and ELISA. The vaccine MAX449 could induce high titer of C5a antibodies and effectively suppress tumor growth in multiple mouse models. Furthermore, MAX449 significantly boosted the effectiveness of anti-PD1 therapy. It not only inhibited the migration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment through downregulating CCRL2 expression via the NF-κB signaling pathway but also reduced the immunosuppressive function of PMN-MDSCs by decreasing IL-1β production through the same pathway. Following vaccine administration, a significant expansion of anti-tumor CD8⁺ T cells was observed. Most importantly, the vaccine proved to augment the antitumor efficacy of programmed death-1 (PD-1) antibodies in cold and hot tumor mouse models. This research demonstrated that MAX449 induced C5a antibodies, which block C5a-C5aR pathway in PMN-MDSCs, suppression of their migratory and immunosuppressive functions, and consequent antitumor activity. Meanwhile, MAX449 boosted the therapeutic efficacy of PD-1 antibody in hot and cold tumor model mice. This study provides compelling evidence supporting the clinical evaluation of MAX449 as an innovative therapeutic approach for cancer.