Anti-PD-L2 immunotherapy is efficacious against melanoma in aged hosts through IL-17 and IFNγ signalling

Area of Science:

• Immunology
• Cancer Biology
• Aging Research

Background:

• Programmed cell death protein 1 (PD-1) and its ligands (PD-L1, PD-L2) are key immune checkpoints.
• Antibodies targeting PD-L1 (αPD-L1) are established cancer immunotherapies.
• The therapeutic potential of antibodies targeting PD-L2 (αPD-L2) remains underexplored, particularly concerning age-related efficacy.

Purpose of the Study:

• To investigate the efficacy of αPD-L2 therapy in young versus aged mice bearing B16 melanoma.
• To elucidate the mechanisms underlying age-dependent αPD-L2 efficacy, focusing on the role of IL-17.
• To explore potential strategies for enhancing αPD-L2 immunotherapy.

Main Methods:

• Comparison of αPD-L2 efficacy in young and aged B16 melanoma-bearing mice.
• Assessment of tumor-infiltrating immune cells (IFN-γ+) and cytokine production.
• Evaluation of IL-17's role using IL-17-deficient mice and exogenous IL-17 administration.
• Testing αPD-L2 efficacy in different tumor models and age groups.

Main Results:

• αPD-L2 was effective in aged mice but not young mice with B16 melanoma.
• Efficacy in aged mice correlated with increased tumor-infiltrating interferon-γ+ cells and IFN-γ production, dependent on IL-17.
• αPD-L2 efficacy improved with age in another tumor type.
• Exogenous IL-17 restored αPD-L2 efficacy in young mice, highlighting IL-17's crucial role in aged immune responses.

Conclusions:

• αPD-L2 immunotherapy exhibits age-dependent efficacy, being more effective in aged hosts.
• IL-17 signaling is a critical mediator of αPD-L2 efficacy in aged melanoma-bearing mice.
• Understanding the age-related mechanisms of αPD-L2 response can inform strategies to improve cancer immunotherapy, including for younger patients and resistant tumors.