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Updated: Aug 8, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
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Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint blockade cancer immunotherapy efficacy
Myrna G Garcia1,2, Yilun Deng3, Clare Murray1,2
1South Texas Medical Scientist Training Program, University of Texas Health, San Antonio, Texas, USA.
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.
Insights
Aging impacts immune checkpoint expression, affecting cancer immunotherapy (ICI) outcomes. Understanding these age-related changes is crucial for optimizing ICI efficacy in older populations.
Area of Science:
- Immunology
- Cancer Research
- Gerontology
Background:
- Aging is the primary risk factor for cancer.
- Immune checkpoint inhibition (ICI) is a key cancer immunotherapy strategy.
- Limited data exist on aging's impact on ICI efficacy and immune checkpoint expression.
Purpose of the Study:
- To investigate age-related changes in immune checkpoint expression across different organs and tumors.
- To elucidate how aging affects the efficacy of different ICI treatments (αPD-1 and αPD-L1).
- To explore the mechanisms underlying age-related differences in ICI response.
Main Methods:
- Flow cytometry was used to assess immune checkpoints on various cells in young and aged mice.
- Experiments included comparisons between wild-type and interferon-γ knockout mice, and tumor-challenged mice treated with ICI.
- In vitro co-culture of young and aged T cells and myeloid cells was performed, with OMIQ analysis for cell-cell interactions.
Main Results:
- αPD-1 ICI was effective in both young and aged hosts, while αPD-L1 ICI was effective only in young hosts.
- Significant age-dependent alterations in immune checkpoint molecules (PD-1, PD-L1, PD-L2, CD80) were observed in various organs and tumors.
- Host interferon-γ levels and tumor challenge influenced age-related immune checkpoint expression.
Conclusions:
- Immune checkpoint expression varies with age in an organ- and tissue-specific manner, with generally higher levels on aged immune cells.
- Elevated PD-1 on aged immune cells may explain αPD-1 efficacy, while CD80/PD-L1 co-expression on dendritic cells might explain αPD-L1 non-efficacy in aged hosts.
- Additional factors beyond myeloid cells and interferon-γ influence age-related immune checkpoint expression and T cell function, warranting further research.
