Reprogramming macrophage by targeting VEGF and CD40 potentiates OX40 immunotherapy

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• Checkpoint blockade therapies (e.g., PD-1, CTLA-4) have limited clinical response rates.
• Agonistic antibodies are needed to enhance T cell responses.
• OX40 is a co-stimulatory receptor crucial for T cell survival and differentiation, but anti-OX40 antibodies have shown limited efficacy.

Purpose of the Study:

• To investigate the mechanisms behind anti-OX40 agonist activity in improving anti-tumor efficacy.
• To analyze dynamic changes in tumor-infiltrating immune cells following anti-OX40 treatment.
• To identify potential combination targets to enhance anti-OX40 therapy.

Main Methods:

• Single-cell RNA-sequencing (scRNA-seq) was used to analyze tumor-infiltrating immune cells at various time points post-treatment.
• Dynamic changes in regulatory T cells (Tregs), CD8+ effector T cells, and M1 macrophages were assessed.
• The role of vascular endothelial growth factor (VEGF) and CD40 signaling pathways in macrophages was investigated.

Main Results:

• Anti-OX40 treatment reduced tumor-infiltrating Tregs after two rounds.
• Increased infiltration and activation of CD8+ effector T cells and M1 polarization were observed after three rounds.
• Dynamic changes in macrophage VEGF and CD40 signaling were identified as potential combination targets.

Conclusions:

• Sequential administration of anti-OX40 agonists leads to delayed but significant anti-tumor immune responses.
• Targeting macrophage VEGF and CD40 signaling pathways can enhance anti-OX40 efficacy.
• Combination strategies using anti-OX40 agonists with VEGFR inhibitors or anti-CD40 agonists show significant tumor growth inhibition.