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

Abstract

Abstract 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.