Combining DNA Vaccine and AIM2 in H1 Nanoparticles Exert Anti-Renal Carcinoma Effects via Enhancing Tumor-Specific Multi-functional CD8+ T-cell Responses

Abstract

Renal carcinoma presents a rapid progression in patients with high metastasis with no effective therapeutic strategy. In this study, we designed a folate-grafted PEI600-CyD (H1) nanoparticle-mediated DNA vaccine containing an adjuvant of absent in melanoma 2 (AIM2) and a tumor-specific antigen of carbonic anhydrase IX (CAIX) for renal carcinoma therapy. Mice bearing subcutaneous human CAIX (hCAIX)-Renca tumor were intramuscularly immunized with H1-pAIM2/pCAIX, H1-pCAIX, H1-pAIM2, or Mock vaccine, respectively. The tumor growth of hCAIX-Renca was significantly inhibited in H1-pAIM2/pCAIX vaccine group compared with the control group. The vaccine activated CAIX-specific CD8 þ T-cell proliferation and CTL responses, and enhanced the induction of multi-functional CD8 þ T cells (expressing TNF-a, IL-2, and IFN-g).CD8 þ T-cell depletion resulted in the loss of anti-tumor activity of H1-pAIM2/pCAIX vaccine, suggesting that the efficacy of the vaccine was dependent on CD8 þ T-cell responses. Lung metastasis of renal carcinoma was also suppressed by H1-pAIM2/pCAIX vaccine treatment accompanied with the increased percentages of CAIX-specific multi-functional CD8 þ T cells in the spleen, tumor, and bronchoalveolar lavage as compared with H1-pCAIX vaccine. Similarly, the vaccine enhanced CAIX-specific CD8 þ T-cell proliferation and CTL responses. Therefore, these results indicated that H1-pAIM2/pCAIX vaccine exhibits the therapeutic efficacy of anti-renal carcinoma by enhancing tumor-specific multi-functional CD8 þ T-cell responses. This vaccine strategy could be a potential and promising approach for the therapy of primary solid or metastasis tumors.

The complex role of AIM2 in autoimmune diseases and cancers

“…T cell reactivity against AIM2 has been found in patients with melanoma, suggesting that AIM2‐derived peptides are an ideal candidate for immunomonitoring 95 . Indeed, as a sensor of DNA, AIM2 induces an antigen‐specific antibody response and is used as an adjuvant to enhance therapeutic efficacy through CD8 + T cell adaptive immunity 39–42 . For example, AIM2 promotes the multifunctional CD8 + T cell activation elicited by the viral capsid protein 1 vaccine, 39 which favors long‐lasting protection against Coxsackievirus B 3 ‐induced myocarditis 40 .…”

“…For example, AIM2 promotes the multifunctional CD8 + T cell activation elicited by the viral capsid protein 1 vaccine, 39 which favors long‐lasting protection against Coxsackievirus B 3 ‐induced myocarditis 40 . Similarly, AIM2‐adjuvant vaccines exhibit antitumor therapeutic efficacy by heightening tumor‐specific CD8 + T cell immunity 41 . The involvement of AIM2 in vaccine‐induced immune responses requires type I IFN signaling via cGAS‐independent STING‐IRF7 signaling 96 .…”

“…Restoration of AIM2 inhibits tumor proliferation, migration, and invasion while enhancing cell apoptosis by inducing autophagy‐related gene expression 15 . Additionally, the DNA vaccine‐containing renal carcinoma specific antigen carbonic anhydrase IX and AIM2 adjuvant, which promotes cells overexpressing inflammasome components and proinflammatory cytokines, can prevent tumor growth 41,129 . Thus, AIM2 is regarded as a tumor‐impressive factor and used as an adjuvant to attenuate renal carcinoma.…”

Inflammasome-Mediated Immunogenicity of Clinical and Experimental Vaccine Adjuvants

“…Vault NPs Large cytoplasmic ribonucleoprotein particles NLRP3 [32] Chitosan Biodegradable cationic polymer obtained from chitin NLRP3 [10,[33][34][35][36] Silica particles Biocompatible particles NLRP3 [37,38] Gold NPs Gold nanoparticles NLRP3 [39] Flagellin Used as recombinant protein, or encoded in virus replicon or DNA plasmid NLRC4 [40][41][42][43][44] DNA vaccines DNA plasmids or Aim2 encoded in vector as immunopotentiator AIM2 [45][46][47] CTB Cholera toxin B from Vibrio cholerae, added to an Ag, or as a DNA vaccine NLRP3, Pyrin [48][49][50] oxPAPC Oxidized 1-palmitoyl-2-arachidonoyl-snglycero-3-phosphorylcholine (generated during tissue damage)…”

“…Interestingly, IFN-α/β were reduced in Aim2-deficient mice after DNA vaccination, which might indicate that DNA vaccines induce IFN-α/β signalling, thereby promoting dispensability of IL-1/IL-18 signalling [46]. Recently, two studies demonstrated that DNA vaccines encoding the Aim2 gene itself might be a promising approach to enhance immunogenicity [45,47].…”