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Updated: Feb 21, 2026
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Impaired PD-1 expression in tumor-infiltrating senescent CD8+ T cells is reversed by PD-L1 blockade in a murine
Yi Lu1, Yuya Su2, Yuto Nagatomo3
1Department of Oral Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (SCIENCE TOKYO), Tokyo, 113-8549, Japan; Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8549, Japan; Oral Science Center, Institute of Science Tokyo (SCIENCE TOKYO), Tokyo, 113-8549, Japan.
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 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.
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.
Insights
Aging impairs antitumor immunity in head and neck squamous cell carcinoma (SCC) by altering the tumor microenvironment. Immune checkpoint inhibitor (ICI) therapy shows differential effects in aged mice, highlighting age-related immune changes.
Area of Science:
- Immunology
- Oncology
- Aging Research
Background:
- Aging is associated with immune system alterations that can impair antitumor immunity and reduce the efficacy of cancer treatments like immune checkpoint inhibitors (ICIs).
- Head and neck squamous cell carcinoma (SCC) is a significant health concern, and ICIs targeting programmed cell death-1 (PD-1) are approved for recurrent and metastatic cases.
- Understanding how aging impacts the tumor immune microenvironment (TME) is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the effects of aging on the tumor immune microenvironment in a murine SCC model.
- To determine how aging modulates the efficacy of anti-PD-1/PD-L1 therapy in SCC.
- To elucidate age-related changes in immune cell populations and their functions within the TME.
Main Methods:
- Analysis of SCCVII tumor growth, tumor-draining lymph node (TDLN) cells, and tumor-infiltrating leukocytes in young, middle-aged, and aged mice.
- Assessment of CD206+ M2-like tumor-associated macrophage (TAM) accumulation and CD8+ T cell (CD8T) phenotypes.
- Evaluation of anti-PD-1 ligand-1 (PD-L1) antibody treatment effects in young and aged mice, including PD-1 expression and IFN-γ production.
Main Results:
- Tumor growth accelerated with age, correlating with increased M2-like TAMs.
- Aged mice showed increased CD8T, interferon (IFN)-γ, and PD-1 expression in lymph nodes, but impaired PD-1 expression on CD8T within the TME.
- Anti-PD-L1 treatment enhanced antitumor immunity in aged mice but preferentially increased PD-1+ CD8T, suggesting age-dependent mechanisms of action for PD-L1 blockade.
Conclusions:
- Aging impairs antitumor immune responses in SCC, characterized by M2-like TAM recruitment and altered CD8T function within the TME.
- PD-1 expression on CD8T in the aged TME is impaired, yet PD-L1 blockade can increase it, indicating differential therapeutic targets or responses based on age.
- These findings underscore the importance of considering age-related immune changes when developing and applying ICI therapies for SCC.
