Enhanced Antitumor Immunity Through T Cell Activation with Optimized Tandem Double-OX40L mRNAs

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• The tumor immune microenvironment (TIME) is often immunosuppressive, hindering effective cancer therapies.
• Dysfunctional TIME contributes to tumor metastasis and resistance to existing treatments.

Purpose of the Study:

• To investigate mRNA-based cancer agents for reversing refractory TIME conditions.
• To engineer and evaluate an optimized mRNA agent encoding double OX40L (diOX40L) for enhanced antitumor effects.

Main Methods:

• Engineered diOX40L mRNA encapsulated in lipid nanoparticles (LNPs).
• In vivo and in vitro experiments to assess safety and efficacy.
• Analysis of T cell activation, cytokine secretion, and tumor growth.

Main Results:

• Optimized diOX40L mRNA efficiently expressed increased OX40L protein levels.
• diOX40L treatment led to decreased tumor growth and improved survival.
• Enhanced CD4+ and CD8+ T cell activation, increased IFN-γ and IL-2 secretion, and robust immune responses.
• Combination therapy with PD-1 antibodies significantly boosted antitumor efficacy.

Conclusions:

• The optimized diOX40L mRNA cancer agent demonstrates significant therapeutic potential in cancer treatment.
• mRNA-based agents offer an innovative alternative to protein-based therapies for modulating the TIME.
• This approach enhances antitumor responses by reactivating the immune system within the tumor microenvironment.