Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Combination immunotherapy, targeting both T-cell checkpoints and myeloid cells, shows promise for aggressive cancers.
• High toxicity of current combination regimens limits clinical application.

Purpose of the Study:

• To evaluate low-dose intratumoral delivery of T-cell checkpoint modulators (CTLA-4, PD-1, 4-1BB) and myeloid agonists (STING, Flt3) in a prostate cancer model.
• To determine if local delivery can achieve systemic control of multifocal disease.

Main Methods:

• Utilized the TRAMP-C2 prostate cancer model in mice.
• Administered combinations of T-cell checkpoint antibodies and myeloid agonists (STING agonist cyclic di-GMP [CDG] or Flt3 Ligand [Flt3L]) intratumorally and systemically.
• Assessed therapeutic efficacy, immune cell infiltration, and tumor-associated macrophage phenotypes.

Main Results:

• Intratumoral STING agonist (CDG) or Flt3L augmented systemic triple checkpoint blockade, curing 75% of mice with bilateral tumors.
• Local CDG, but not Flt3L, with systemic checkpoint blockade mobilized abscopal immunity.
• Combination therapy increased CD8+ T cells, decreased regulatory T cells (Tregs) and myeloid-derived suppressor cells, and shifted macrophages to an anti-tumor phenotype.
• Reduced CDG dosing mitigated injection site ulceration without sacrificing efficacy.

Conclusions:

• Local administration of STING agonists combined with systemic checkpoint blockade provides substantial systemic benefit and minimizes immune-related adverse events.
• Optimizing dosing and delivery routes is crucial for maximizing combination immunotherapy efficacy and safety in aggressive cancers.