Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Prostate cancer (PCa) is a "cold tumor" resistant to immune checkpoint inhibitors (ICI) due to limited immune responses.
• Therapeutic messenger RNA (mRNA) vaccines offer a strategy to enhance immune reactivity against tumors.

Purpose of the Study:

• To evaluate the efficacy of a novel mRNA vaccine (Tetra) combined with an immune-enhancing adjuvant (ImmunER) for inducing anti-tumor immunity in PCa.
• To investigate the underlying mechanisms of Tetra + ImmunER in modulating immune cells and anti-tumor responses.

Main Methods:

• Synthesis of Tetra mRNA vaccine with multiple tumor-associated antigens and ImmunER adjuvant.
• Assessment of ImmunER's effects on dendritic cell (DC) maturation, migration, and antigen presentation in vitro and in vivo.
• Analysis of Tetra + ImmunER's impact on DC phenotype, cytokine release (IL-12, TNF-α), JAK-STAT1 pathway activation, and T cell responses.
• In vivo evaluation of Tetra + ImmunER in RM-1-PSMA tumor models, assessing CD8+ T cell infiltration and activation.

Main Results:

• ImmunER promoted DC maturation, migration, and antigen presentation.
• Tetra + ImmunER induced cDC1-CCL22 transformation and activated the JAK-STAT1 pathway, leading to increased IL-12 and TNF-α production.
• The combination therapy enhanced T cell proliferation, activation, and tumor cell killing.
• In vivo studies showed increased CD8+ T cell infiltration and activation within RM-1-PSMA tumors treated with Tetra + ImmunER.

Conclusions:

• The integrated Tetra and ImmunER mRNA-LNP therapy demonstrates significant potential for overcoming immune resistance in prostate cancer.
• This combination strategy effectively enhances anti-tumor immunity by modulating dendritic cells and T cell responses.
• Tetra + ImmunER represents a promising therapeutic approach for treating "cold tumor" types like prostate cancer.