Boosting innate and adaptive antitumor immunity via a biocompatible and carrier-free nanovaccine engineered by the bisphosphonates-metal coordination

Abstract

• First calcium-bisphosphonates coordination nanovaccine that boosts both innate and adaptive antitumor immunity. • The combination of nanovaccine and anti-PD-1 achieved a 50% total disappearance of tumor. • The biocompatible nanocarriers could enlarge the innate immunity of bisphosphonates. A calcium-bisphosphonates coordination nanovaccine system was developed to co-deliver bisphosphonates (BPs), tumor antigens and lipid A. In vitro, BPs, as the main part of the carrier-free nanovaccine, promoted the proliferation of γδT cells and stimulated the secretion of IFN-γ and granzyme B. BPs in nanovaccine were also found to stimulate the proliferation of DCs. In vivo, nanovaccine was injected subcutaneously and accumulated in draining LNs. The nanovaccine enhanced DCs maturation and antigen presenting. Antigen specific cytotoxic T cells were induced, subsequently infiltrated into tumors and triggered tumor cells specific lysis. Besides, the anti-tumor efficacy of the nanovaccine was enhanced after combined with PD-1 antibody. Here, OVA 257–280 was used as a model antigen to evaluate the characteristics, innate and adaptive immune activation effect, in vivo tumor prophylactic and therapeutic efficacy of the nanovaccine. To further investigate the application of CaBPs as a vaccination platform for other antigens, the CaBPs/neoantigens nanovaccine (CaBPs/NAg) which contained a cocktail of tumor associated antigen (Trp2 173–196 ) and neoantigens (M27 and M30) was also tested here. Finally, the PD-1 antibody was applied together with the nanovaccine to further verify the anti-tumor efficacy. Most of tumor vaccines currently focus on inducing adaptive immunity, while the antitumor potential of innate immunity is getting more attentions. In an attempt to recruit both innate and adaptive immunity, bisphosphonates (BPs) as a type of orthopaedics drugs with biosafety was applied in an antitumor vaccine here as an innate immune regulator. BPs and calcium themselves shaped the biodegradable nanocarrier via their coordination (CaBPs), which could load peptide antigens due to its hydrophilicity and be stabilized by surface lipids including a TLR4 agonist (nanovaccine). As results, the incorporation of BPs triggered the proliferation and activation of DCs and innate-like γδT cells, while the nanovaccine enhanced antigen presentation and specific lysis of tumor cells. The combination of nanovaccine and anti-PD-1 achieved a 50% total disappearance of tumor. In a prophylactic study, no any tumor occurred in nanovaccine group during a 110 day study with 3 time tumor challenges. Generally, this study validates the double antitumor immunities and provides a very promising approach for clinic application.