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.

Rationale: 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. Methods: 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. Results: 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. Conclusions: 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.