Impaired PD-1 expression in tumor-infiltrating senescent CD8+ T cells is reversed by PD-L1 blockade in a murine squamous cell carcinoma model.
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.
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.
Tumor growth accelerated with age and was accompanied with increased CD206+ M2-like tumor-associated macrophage (TAM) accumulation. In intact LNs and TDLNs, CD8+ T 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-1-IFN-γ- CD8T predominated in aged mice, whereas PD-1+IFN-γ- CD8T predominated in young mice. Anti-PD-L1 treatment in aged mice enhanced antitumor immunity, but preferentially increased PD-1+ CD8T in both TDLNs and TME.
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.
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.
Tumor growth accelerated with age and was accompanied with increased CD206+ M2-like tumor-associated macrophage (TAM) accumulation. In intact LNs and TDLNs, CD8+ T 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-1-IFN-γ- CD8T predominated in aged mice, whereas PD-1+IFN-γ- CD8T predominated in young mice. Anti-PD-L1 treatment in aged mice enhanced antitumor immunity, but preferentially increased PD-1+ CD8T in both TDLNs and TME.
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.
Authors
Lu Lu, Su Su, Nagatomo Nagatomo, Zhang Zhang, Nagai Nagai, Nishii Nishii, Harada Harada, Lin Lin, Katagiri Katagiri, Azuma Azuma
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