Nucleic acid vaccination strategies for ovarian cancer

Abstract

High grade serous carcinoma (HGSC) is one of the most lethal ovarian cancers that is characterised by asymptomatic tumour growth, insufficient knowledge of malignant cell origin and sub-optimal detection. HGSC has been recently shown to originate in the fallopian tube and not in the ovaries. Conventional treatments such as chemotherapy and surgery depend upon the stage of the disease and have resulted in higher rates of relapse. Hence, there is a need for alternative treatments. Differential antigen expression levels have been utilised for early detection of the cancer and could be employed in vaccination strategies using nucleic acids. In this review the different vaccination strategies in Ovarian cancer are discussed and reviewed. Nucleic acid vaccination strategies have been proven to produce a higher CD8⁺ CTL response alongside CD4⁺ T-cell response when compared to other vaccination strategies and thus provide a good arena for antitumour immune therapy. DNA and mRNA need to be delivered into the intracellular matrix. To overcome ineffective naked delivery of the nucleic acid cargo, a suitable delivery system is required. This review also considers the suitability of cell penetrating peptides as a tool for nucleic acid vaccine delivery in ovarian cancer.

Keywords: DNA; high grade serous carcinoma; mRNA; nucleic acid vaccines; ovarian cancer; tumour antigens.

FIGURE 1

Ovarian Cancer types. All tumours associated with OC have been broadly classified into two subtypes: Type I and Type II. Malignant Type II comprises >85% of the total OC.

FIGURE 2

The origin of HGSC OC, most common form of EOC. A precursor lesion known as serous tubal intraepithelial carcinoma (STIC) in the fallopian tube are considered as the site for the origin of the malignant cells and involve the ovaries only secondarily (Created in BioRender.com).

FIGURE 3

Cells in the tumour microenvironment. (A) High number of T_regs and MDSCs help in proliferation of the tumour cells evading the immune surveillance (B) Use of immunotherapy can increase the CTL in the tumour microenvironment thereby leading to decrease in the tumour growth by cell apoptosis. (Created with BioRender.com).

FIGURE 4

DNA vaccine targeting DC cells to induce an immune response. The vaccine is delivered intradermally where the immature APC, macrophages and other immune cells are recruited. The cargo enters the immature APC, traffics to the nucleus where the RNA transcription occurs followed by protein translation in the cytoplasm and is then represented on the cellular surface as MHC I and thus matures the DC. These cells then trigger the CD8⁺CTL response. However, if the plasmid is taken up by the non-APC cells, they either present them in MHC I and subsequently release the antigenic peptide on apoptosis or directly release the peptide by proteolysis by proteosome. These peptides are then taken up by the APC and either cross presented in MHC I or presented on MHC II which stimulates the CD4⁺ T cell response which further generates CD8⁺ CTL and memory cells. (Created with BioRender.com).

FIGURE 5

RALA Nanoparticle formation. The cationic RALA peptide forms a self-assembled nanoparticle with a negatively charged nucleic acid cargo due to the electrostatic interaction between them. The resultant nanoparticle is expected to have a positive charge due to the neutralization of the negative charge of the nucleic acid by the positively charged RALA.