Universal immunotherapeutic strategy for hepatocellular carcinoma with exosome vaccines that engage adaptive and innate immune responses

Abstract

Background Personalized immunotherapy utilizing cancer vaccines tailored to the tumors of individual patients holds promise for tumors with high genetic heterogeneity, potentially enabling eradication of the tumor in its entirety. Methods Here, we demonstrate a general strategy for biological nanovaccines that trigger tailored tumor-specific immune responses for hepatocellular carcinoma (HCC). Dendritic cell (DC)-derived exosomes (DEX) are painted with a HCC-targeting peptide (P47-P), an α-fetoprotein epitope (AFP212-A2) and a functional domain of high mobility group nucleosome-binding protein 1 (N1ND-N), an immunoadjuvant for DC recruitment and activation, via an exosomal anchor peptide to form a “trigger” DEX vaccine (DEXP&A2&N). Results DEXP&A2&N specifically promoted recruitment, accumulation and activation of DCs in mice with orthotopic HCC tumor, resulting in enhanced cross-presentation of tumor neoantigens and de novo T cell response. DEXP&A2&N elicited significant tumor retardation and tumor-specific immune responses in HCC mice with large tumor burdens. Importantly, tumor eradication was achieved in orthotopic HCC mice when antigenic AFP peptide was replaced with the full-length AFP (A) to form DEXP&A&N. Supplementation of Fms-related tyrosine kinase 3 ligand greatly augmented the antitumor immunity of DEXP&A&N by increasing immunological memory against tumor re-challenge in orthotopic HCC mice. Depletion of T cells, cross-presenting DCs and other innate immune cells abrogated the functionality of DEXP&A&N. Conclusions These findings demonstrate the capacity of universal DEX vaccines to induce tumor-specific immune responses by triggering an immune response tailored to the tumors of each individual, thus presenting a generalizable approach for personalized immunotherapy of HCC, by extension of other tumors, without the need to identify tumor antigens.

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

“…Except for liver-, lung- and lymph node-specific delivery of RNA, the specific delivery of RNA to other organs after intravenous administration may enhance the utility of LNPs. In addition, extracellular vesicles (EVs) are an emerging platform for delivering siRNA, peptides or proteins [ 166 , 167 ]. EVs from red blood cells have been successfully used for intratumoral delivery of 5'-pppRNA as RIG-I agonist [ 168 ].…”

Roles of exosomes as drug delivery systems in cancer immunotherapy: a mini-review

“…Zhen et al reported that alpha-fetoprotein (AFP)-expressing Dex could induce potent antigen-specific immune responses in ectopic or orthotopic hepatocellular carcinoma (HCC) mice, improved the immune microenvironment of autologous tumors, and decrease the amount of immune stimulation cell and CD8+ CTL infiltration, levels of immunosuppressive cytokines and the number of Treg cells [ 149 ]. A recent study reported that Dex vaccine (DEX P&A2&N ) promoted the recruitment and activation of DCs in mice with liver cancer, thereby enhancing tumor-specific immune responses [ 150 ]. Studies have reported that DC cell-derived exosomes can cross the BBB to deliver RNAi to the brain and play a biological role, such as inhibiting tumor growth [ 151 ].…”

Dendritic-Cell-Vaccine-Based Immunotherapy for Hepatocellular Carcinoma: Clinical Trials and Recent Preclinical Studies

“…The results showed that the DC-based nanoparticle vaccine induced stronger IFN-γ-producing CTL-mediated cytotoxicity against the H22 cell line in vitro and exhibited better efficacy in suppressing tumor growth and prolonging survival in an ectopic allograft immunocompromised BALB/c mouse model than non-DC-based nanoparticle vaccine when combined with laser irradiation. Another study performed by Zuo et al evaluated the efficacy of a DC-derived exosome vaccine, which was prepared by co-conjugating an immortalized DC-line-derived exosome with an AFP-derived epitope AFP 212 , an HCC tumor-targeting peptide P47, and a functional domain of high mobility group nucleosome-binding protein 1 (HMGN1), an immunoadjuvant capable of promoting DC recruitment and activation, in treating HCC [ 61 ]. The results showed that the DC-derived exosome vaccine exhibited efficient efficacy in suppressing tumor growth and prolonging survival in both ectopic and orthotopic allograft immunocompetent C57BL/6 mouse models of the mouse HCC cell line Hepa1-6.…”