Innate immunity: Looking beyond T-cells in radiation and immunotherapy combinations.

Area of Science:

• Oncology
• Immunology
• Radiotherapy

Background:

• Radiation therapy is a cornerstone of cancer treatment, known to modulate the immune system.
• Pre-clinical data suggest synergy between radiation and checkpoint immunotherapy, mediated by immune cell recruitment and activation.
• However, clinical trials combining radiation and immunotherapy have yielded disappointing results, necessitating a deeper understanding of their interplay.

Approach:

• This review examines the dual role of radiotherapy in modulating innate immune responses.
• It summarizes the impact of radiation on key innate immune cells and immunosuppressive cytokines.
• Focuses on understanding radiotherapy's effects on the innate immune system to optimize radioimmunotherapy.

Key Points:

• Radiation induces DNA breaks, activating pathways like cGAS/STING, producing Type 1 interferons that recruit antigen-presenting cells (APCs).
• It promotes CD8 T-cell infiltration by releasing tumor antigens, enhancing adaptive immunity.
• Conversely, radiation recruits immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressive cells (m-MDSCs), which express immune checkpoints (e.g., PD-L1).

Conclusions:

• Radiotherapy has complex, often opposing, effects on the immune system, presenting both immunostimulatory and immunosuppressive properties.
• Optimizing radioimmunotherapy requires a comprehensive understanding of how radiation impacts innate immune cells and their suppressive functions.
• Further research into these interactions is crucial for improving the efficacy of combined treatment strategies.