Dual-targeting vaccine of FGL1/CAIX exhibits potent anti-tumor activity by activating DC-mediated multi-functional CD8 T cell immunity

Abstract

Tumor DNA vaccine as an effective therapeutic approach can induce systemic immunity against malignant tumors, but its therapeutic effect is still not satisfactory in advanced renal cancer. Herein, a novel DNA vaccine containing dual antigens of fibrinogen-like protein 1 (FGL1) and carbonic anhydrase IX (CAIX) was developed and intramuscularly delivered by PLGA/PEI nanoparticles for renal cancer therapy. Compared with PLGA/PEI-pCAIX immunization, PLGA/PEI-pFGL1/pCAIX co-immunization significantly inhibited the subcutaneous tumor growth and promoted the differentiation and maturation of CD11c + DCs and CD11c + CD11b + DCs subset. Likewise, the increased capabilities of CD8 T cell proliferation, CTL responses, and multi-functional CD8 + T cell immune responses were observed in PLGA/PEI-pFGL1/pCAIX vaccine group. Interestingly, depletion of CD8 + T cells by using CD8 mAb resulted in a loss of anti-tumor function of PLGA/PEI-pFGL1/pCAIX vaccine, suggesting that the anti-tumor activity of the vaccine was dependent on CD8 + T cell immune responses. Furthermore, PLGA/PEI-pFGL1/pCAIX co-immunization also suppressed the lung metastasis of tumor mice by enhancing the multi-functional CD8 + T cell responses. Therefore, these results indicate that PLGA/PEI-pFGL1/pCAIX vaccine could provide an effective protective effect for renal cancer by enhanced DC-mediated multi-functional CD8 + T cell immune responses. This vaccine strategy offers a potential approach for solid or metastatic tumor treatment.

HMGB1/GPC3 dual targeting vaccine induces dendritic cells-mediated CD8+T cell immune response and elicits potential therapeutic effect in hepatocellular carcinoma

“…Our previous study has demonstrated that PLGA/PEI-mediated DNA delivery system is able to promote DNA vaccine to penetrate the biological barriers and transfer the plasmid into the nucleus of the target cell to express it stably. 31 In this study, our result also demonstrated that PLGA/PEI-HMGB1/GPC3 vaccine could be efficiently expressed in vitro and in vivo . The immunogenicity and therapy effect of the PLGA/PEI-HMGB1/GPC3 vaccine was evaluated in the HCC model.…”

“… 41 PLGA/PEI-mediated DNA vaccine could also shield the delivered antigens from degradation to further improve their uptake into DCs and induce the maturity of DCs. 31 The results of the present study showed that PLGA/PEI-HMGB1/GPC3 vaccine can significantly promote the ratio of CD8 + DCs and CD103 + DCs, thus indicating that the nanoparticle can sufficiently bolster the magnitude of the CTL effect via DCs-mediated anti-tumor response. In addition, the design of a vaccine strategy targeting DCs might offer great promise for enhancing the immune response against the tumor.…”

“…Previous study has confirmed that PLGA/PEI-based encapsulation of antigen sequence displayed no toxic effect and was highly proficient in DNA delivery. 31 Our results showed that the PLGA-PEI-based nanoparticles can mediate the expression of both adjuvant molecules and antigens in vivo and thus can contribute to the induction of remarkable therapeutic effects. In the course of these experiments, no abnormal inflammatory changes were observed in mice immunized with vaccines, which confirmed the biosafety of the PLGA/PEI-HMGB1/GPC3 nanoparticle vaccine.…”

The regulation role and diagnostic value of fibrinogen-like protein 1 revealed by pan-cancer analysis

“…An increasing number of studies have strongly suggested that FGL1 is highly expressed in various tumor tissues and may serve as a pan-cancer prognostic biomarker [ 8 , 12 , 17 ]. Recent studies have shown that targeting FGL1 may serve as a new strategy for tumor immunotherapy [ 18 , [32] , [33] , [34] , [35] ]. However, the molecular mechanisms of FGL1 in different cancer types remain unclear and require further investigation.…”

Advancing together and moving forward: Combination gene and cellular immunotherapies

“…These therapies target the innate immunity that aims to present tumor antigens to cytotoxic T cells to stimulate anti-tumor responses. In this issue, Chai et al 8 developed a novel dual-targeting DNA-based vaccine, specifically for fibrinogen like 1 and carbonic anhydrase IX antigens for renal cell cancers, by targeting dendritic cell subsets to generate multi-functional CD8 + T cell responses against metastasis. Yeo et al 9 reviewed the challenges facing immunotherapy for treating patients with pancreatic cancer that is notoriously resistant to most therapeutic interventions, including cell-based therapies.…”