Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint blockade cancer immunotherapy efficacy in aged versus young mice

Introduction: Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors. Methods: Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon-γ^KO mice and WT challenged with B16F10 melanoma and treated with αPD-1 or αPD-L1 ICI. We co-cultured young and aged T cells and myeloid cells in vitro and used OMIQ analyses to test cell–cell interactions. Results: αPD-1 ICI treated melanoma in young and aged hosts, whereas αPD-L1 ICI was only effective in young. We found considerable, previously undescribed age effects on expression of various IC molecules participating in the ICI treatment, including PD-1, PD-L1, PD-L2, and CD80, in distinct organs and in the tumor. These data help explain differential ICI efficacy in young and aged hosts. Host interferon-γ influenced age effects on IC expression in both directions depending on specific IC molecule and tissue. IC expression was further affected by tumor challenge on immune, non-immune, and tumor cells in tumor and other organs. In in vitro co-culture, αPD-1 versus αPD-L1 distinctly influenced polyclonal T cells in young versus aged, suggesting mechanisms for distinct age-related ICI outcomes. Conclusion: Age affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain αPD-1 efficacy in aged. High co-expression of CD80 with PD-L1 on dendritic cells could help explain lack of αPD-L1 efficacy in aged hosts. Factors other than myeloid cells and interferon-γ also affect age-related IC expression and T cell function, meriting additional studies.