Genetically-engineered “all-in-one” vaccine platform for cancer immunotherapy

Abstract

An essential step for cancer vaccination is to break the immunosuppression and elicit a tumor-specific immunity. A major hurdle against cancer therapeutic vaccination is the insufficient immune stimulation of the cancer vaccines and lack of a safe and efficient adjuvant for human use. We discovered a novel cancer immunostimulant, trichosanthin (TCS), that is a clinically used protein drug in China, and developed a well-adaptable protein-engineering method for making recombinant protein vaccines by fusion of an antigenic peptide, TCS, and a cell-penetrating peptide (CPP), termed an “all-in-one” vaccine, for transcutaneous cancer immunization. The TCS adjuvant effect on antigen presentation was investigated and the antitumor immunity of the vaccines was investigated using the different tumor models. The vaccines were prepared via a facile recombinant method. The vaccines induced the maturation of DCs that subsequently primed CD8 + T cells. The TCS-based immunostimulation was associated with the STING pathway. The general applicability of this genetic engineering strategy was demonstrated with various tumor antigens ( i.e. , legumain and TRP2 antigenic peptides) and tumor models ( i.e. , colon tumor and melanoma). These findings represent a useful protocol for developing cancer vaccines at low cost and time-saving, and demonstrates the adjuvant application of TCS—an old drug for a new application.

Recombinant cell-penetrating trichosanthin synergizes anti-PD-1 therapy in colorectal tumor

“…In our previous work, TCS was applied as a vaccine adjuvant and successfully induced cancer immunization 18 , 19 . But its application as an adjuvant therapy to the mainstay immune checkpoint therapy was not yet revealed.…”

“…The bone marrow-derived dendritic cells (BMDCs) were induced from the bone marrow mononuclear cells derived from BALB/c mice using mGM-CSF (20 ng/ml) and mIL-4 (10 ng/ml), as described in a previous report 18 . The loosely attached immature DCs were collected for the subsequent experiments.…”

“…Notably, TCS can effectively inhibit tumors like fibrosarcoma 14 and glioma 15 , and restore the sensitivity of tumors to chemotherapeutics 16 , 17 . In our lab, we previously revealed that TCS induced anticancer immunity, such as increasing the intratumoral infiltration of CD8 + T cells and stimulating the dendritic cells, thus serving as a vaccination adjuvant 18 , 19 . It suggested the potential of TCS as an immunostimulant to assist immune checkpoint inhibition therapy.…”

A Sixty-Year Research and Development of Trichosanthin, a Ribosome-Inactivating Protein

“…The penetrating peptide (CPP)-fused recombinant TCS toxin conjugated to lactoferrin (LF) has the potential to penetrate the blood–brain barrier (BBB) [ 146 ]. A cancer vaccination platform based on TCS was also implemented in 2021 [ 147 ], which is a promising tool for cancer immunotherapy. In basic science, studies on the TCS-ribosome complex by Cryo-EM will reveal the detail of interaction.…”

Trichosanthin Promotes Anti-Tumor Immunity through Mediating Chemokines and Granzyme B Secretion in Hepatocellular Carcinoma

“…Studies have shown that TCS could enhance the sensitivity of tumors to chemotherapeutic drug treatment [ 13 , 16 ]. Recombinant TCS has shown potent anti-tumor effects [ 17 , 18 , 19 ]. It is crucial to investigate the anti-tumor mechanisms and potential applications of TCS.…”