IRES-based RNAs expressing co-stimulatory molecules: Promising candidates for cancer immunotherapy

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Optimizing co-stimulatory signaling is crucial for enhancing T cell responses in antitumor immunity.
• Current immunotherapies aim to modulate these signaling pathways for improved efficacy.

Purpose of the Study:

• To develop and evaluate single-stranded RNAs (ssRNAs) utilizing the internal ribosome entry site (IRES) of encephalomyocarditis virus (EMCV) to express co-stimulatory molecules (OX40L, 4-1BBL, ICOSL).
• To assess the efficacy of these IRES-based ssRNAs in enhancing T cell responses and suppressing tumor growth in preclinical models.

Main Methods:

• Development of ssRNAs encoding OX40L, 4-1BBL, and ICOSL via EMCV IRES.
• In vitro co-culture assays with splenocytes and tumor cells to assess immune cell activation.
• In vivo studies involving intramuscular and intratumoral delivery of ssRNAs in melanoma mouse models.

Main Results:

• Co-culture with ssRNA-transfected tumor cells increased cytokine production, proliferation, and altered T helper (Th) subsets.
• Intramuscular delivery of ssRNAs expanded antigen-specific CD8+ T cells.
• Intratumoral delivery significantly suppressed tumor growth and led to complete tumor regression in a subset of mice.
• ssRNAs promoted immune cell infiltration, increased cytotoxic CD8+ T cells, and reduced regulatory T cells (Tregs) in lymphoid organs.

Conclusions:

• IRES-based ssRNAs expressing co-stimulatory molecules are effective in enhancing antitumor immunity.
• This ssRNA platform shows significant promise for developing novel cancer immunotherapies.
• The approach modulates the tumor microenvironment and systemic immune responses for therapeutic benefit.