Cell-Penetrating Peptide Enhanced Antigen Presentation for Cancer Immunotherapy

Abstract

The development of effective cancer vaccines is an important direction in the area of cancer immunotherapy. Although certain types of preventive cancer vaccines have already been used in the clinic, therapeutic cancer vaccines for treatment of already established tumors are still in high demand. In this study, we develop a new type of cancer vaccine by mixing cellpenetrating peptide (CPP) conjugated antigen as the enhanced antigen, together with CpG as the immune adjuvant. A special CPP, cytosol-localizing internalization peptide 6 (CLIP6), which has the ability to enter cells exclusively via a nonendosomal mechanism, i.e., direct translocation across the cell membrane, is conjugated with model antigen ovalbumin (OVA). Compared to naked OVA, the obtained CLIP6-OVA conjugates show greatly increased uptake by dendritic cells (DCs) and, more importantly, remarkably enhanced antigen cross-presentation, eliciting stronger cytotoxic T lymphocyte (CTL) mediated immune responses with the help of CpG. This CLIP6-OVA/CpG formulation offers effective protection for mice against challenged B16-OVA tumors, and is able to further function as a therapeutic vaccine, which, in combination with immune checkpoint blockade therapy, can significantly suppress the alreadyestablished tumors. Such a CLIP6-based cancer vaccine developing strategy shows promising potential toward clinical practice owing to its features of easy preparation, low cost, and remarkable biocompatibility.

Transcutaneous Cancer Vaccine Using a Reverse Micellar Antigen Carrier

“…Cancer vaccines, which activate patient’s immune systems to fight against cancer cells, are a promising strategy to prophylactically prevent the onset of cancer and have been extensively investigated over the past decade. − To evoke tumor-specific immunity, cancer antigens should be delivered to dendritic cells (DCs), professional antigen-presenting cells, which play a pivotal role in the immune system. DCs capture, process, and present antigens via the major histocompatible complex (MHC) to naïve T cells, which elicits CD8 + T cell-mediated immune responses that are critical effector cells in cancer vaccines.…”

Targeting Cross-Presentation as a Route to Improve the Efficiency of Peptide-Based Cancer Vaccines

“…The use of CPP as a strategy to enhance vaccine-delivered antigen uptake and cross-presentation in DC is an area of growing research. Originating with sequences identified from nature such as the HIV-derived TAT peptide [ 59 ] and Penetratin [ 60 ], which can shuttle cargos across cell membranes, modern CPPs are now engineered to enhance their cell-penetrating and endosomal escape capabilities [ 13 , 61 ] or to avoid entrapment within endosomes altogether [ 62 ]. This may account for earlier reports suggesting that CPP-linked antigens were no more effective than those undergoing receptor mediated endocytosis for targeting DC for cross-presentation [ 63 ] and our own data, comparing TAT to the 1746 CPP support this.…”

Beyond Just Peptide Antigens: The Complex World of Peptide-Based Cancer Vaccines

“…One example of this was recently developed by a combination of a cell-penetrating peptide (CPP), a TLR2/4 agonist which activates APCs, and a multi-antigenic domain that stimulates CD4 + and CD8 + T cells ( 92 ). The TLR agonist promotes DC maturation and activation, while the cell-penetrating peptide allows the antigenic domain to access the cytosolic compartment of DCs where antigen cross-presentation occurs, increasing production of antigen-specific CD8 + T cells and boosting anti-tumour immunity ( 93 ). With this strategy, in HPV TC-1 therapeutic mouse tumour models, a significant increase in survival time and reduction in tumour size were observed, and in multiple mouse models an increase in antigen-specific CD8 + T cell tumour infiltration ( 92 ).…”