Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent...

Area of Science:

• Immunology
• Oncology
• Molecular Medicine

Background:

• Cancer immunotherapy efficacy is often limited by poor tumor immunogenicity and immunosuppressive tumor microenvironments (TME).
• Reprogramming the TME to create an immune-inflamed tumor phenotype is crucial for enhancing cancer immune responsiveness.
• Flagrp170 is an immune modulator engineered with a pathogen-associated molecular pattern (flagellin) and an immunostimulatory chaperone.

Purpose of the Study:

• To evaluate the immunostimulatory activity and antitumor potency of Flagrp170.
• To investigate the immunological mechanism of action of Flagrp170.
• To assess potential side effects of Flagrp170 treatment.

Main Methods:

• Utilized multiple murine cancer models for evaluating Flagrp170 administered via replication-impaired adenovirus.
• Employed antibody neutralization and mice deficient in pattern recognition receptors (TLR5 and NLRC4) to elucidate the mechanism.
• Assessed Flagrp170's effects on cytokine induction and immune cell mobilization within the TME.

Main Results:

• Intratumoral Flagrp170 demonstrated robust inhibition of head and neck squamous cell carcinoma and breast cancer without toxicity.
• Treatment induced cytokines supporting Th1/Tc1-dominant antitumor immunity and involved granulocyte macrophage colony-stimulating factor from CD8+ T cells.
• NLRC4, not TLR5, was identified as essential for Flagrp170-mediated antitumor immune responses.

Conclusions:

• Flagrp170 exhibits novel immune-potentiating activity by engaging the NLRC4 innate pattern recognition receptor.
• Flagrp170 effectively reshapes the cancer immune phenotype, overcoming therapeutic resistance.
• These findings support the potential clinical application of Flagrp170 for enhancing cancer immunotherapy.