Pattern recognition receptor agonists in pathogen vaccines mediate antitumor T-cell cross-priming.

Area of Science:

• Immunology
• Oncology
• Vaccinology

Background:

• Cancer immunotherapies rely on T-cells reactive to tumor antigens (TA).
• In situ vaccination (ISV) primes T-cells by administering immunostimulants directly to the tumor.
• Current ISV methods use Flt3L, radiotherapy, and synthetic pattern recognition receptor agonists (PRRa), but optimal DC activation is unknown.

Purpose of the Study:

• To identify optimal dendritic cell (DC) activators for ISV.
• To assess pathogen-derived natural PRRa (naPRRa) as clinical-grade reagents for DC activation.
• To elucidate the mechanisms by which naPRRa potentiate T-cell priming.

Main Methods:

• Deep profiling of naPRRa immunomodulatory effects.
• Gene editing of specific PRRs to define molecular mechanisms.
• Assessment of naPRRa combinations for DC activation and T-cell cross-priming in murine and human systems.

Main Results:

• Vaccine naPRRa are more potent DC activators than synthetic PRRa, enhancing T-cell cross-priming.
• A combination of naPRRa (BCG, PedvaxHIB, Rabies) induced superior T-cell cross-priming.
• ISV with naPRRa resulted in increased intratumoral CD8 T-cell infiltration, neoantigen-specific T-cells, and durable tumor regressions.

Conclusions:

• Pathogen vaccine components serve as effective, clinical-grade DC activators for ISV.
• naPRRa offer a promising strategy to enhance cancer immunotherapy efficacy.
• This approach supports the translation of pathogen vaccines into early-phase clinical trials for cancer treatment.