Impaired PD-1 expression in tumor-infiltrating senescent CD8T cells is reversed by PD-L1 blockade in a murine squamous cell carcinoma model.

Abstract

OBJECTIVES: Aging induces senescence-related immune changes that affect antitumor immunity and treatment efficacy. Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) are approved for recurrent and metastatic head and neck squamous cell carcinoma (SCC). We aimed to investigate how aging alters the tumor immune microenvironment and modulates ICI efficacy in a murine SCC model. METHODS: We analyzed SCCVII tumor growth and phenotypes of tumor-draining lymph node (TDLN) cells and tumor-infiltrating leukocytes in young, middle-aged, and aged mice. We examined the effects of antibodies against PD-1 ligand-1 (PD-L1) in young and aged mice. RESULTS: Tumor growth accelerated with age and was accompanied with increased CD206M2-like tumor-associated macrophage (TAM) accumulation. In intact LNs and TDLNs, CD8T cells (CD8T), interferon (IFN)-γ, and PD-1 expression increased with age. The CD8T phenotype in the tumor microenvironment (TME) differed between young and aged mice; however, CD8T and regulatory T cells preferentially recruited to the TME across all age groups. PD-1 expression was significantly impaired in TME of aged mice. PD-1IFN-γCD8T predominated in aged mice, whereas PD-1IFN-γCD8T predominated in young mice. Anti-PD-L1 treatment in aged mice enhanced antitumor immunity, but preferentially increased PD-1CD8T in both TDLNs and TME. CONCLUSIONS: In the SCCVII model, aging impaired the antitumor immune responses, associated with early recruitment of M2-like TAMs. PD-1 expression in aged TME CD8T was impaired, but the PD-L1 blockade increased PD-1 expression, suggesting that the site of action for PD-L1 blockade differs between young and aged mice.