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NK cell transfer overcomes resistance to PD-(L)1 therapy in aged mice
Junlei Hou1, Shuanglong Xie1,2, Jianbao Gao1
1Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
Background:
Cancer is the leading cause of death among older adults. Although the integration of immunotherapy has revolutionized the therapeutic landscape of cancer, the complex interactions between age and immunotherapy efficacy remain incompletely defined. Here, we aimed to elucidate the relationship between aging and immunotherapy resistance.
Methods:
Flow cytometry was performed to evaluate the infiltration of immune cells in the tumor microenvironment (TME). In vivo T cell proliferation, cytotoxicity and migration assays were performed to evaluate the antitumor capacity of tumor antigen-specific CD8+ T cells in mice. Real-time quantitative PCR (qPCR) was used to investigate the expression of IFN-γ-associated gene and natural killer (NK)-associated chemokine. Adoptive NK cell transfer was adopted to evaluate the effects of NK cells from young mice in overcoming the immunotherapy resistance of aged mice.
Results:
We found that elderly patients with advanced non-small cell lung cancer (aNSCLC) aged ≥ 75 years exhibited poorer progression-free survival (PFS), overall survival (OS) and a lower clinical response rate after immunotherapy. Mechanistically, we showed that the infiltration of NK cells was significantly reduced in aged mice compared to younger mice. Furthermore, the aged NK cells could also suppress the activation of tumor antigen-specific CD8+ T cells by inhibiting the recruitment and activation of CD103+ dendritic cells (DCs). Adoptive transfer of NK cells from young mice to aged mice promoted TME remodeling, and reversed immunotherapy resistance.
Conclusion:
Our findings revealed the decreased sensitivity of elderly patients to immunotherapy, as well as in aged mice. This may be attributed to the reduction of NK cells in aged mice, which inhibits CD103+ DCs recruitment and its CD86 expression and ultimately leads to immunotherapy resistance.
Insights
Aging impairs immunotherapy effectiveness by reducing natural killer (NK) cells. This reduction hinders anti-tumor T cell activity, leading to immunotherapy resistance in older adults and aged mice.
Area of Science:
- Immunology
- Oncology
- Geriatrics
Background:
- Cancer remains a leading cause of death in older adults.
- Immunotherapy has advanced cancer treatment, but age-related efficacy is not fully understood.
- Investigating the link between aging and immunotherapy resistance is crucial.
Purpose of the Study:
- To elucidate the relationship between aging and immunotherapy resistance.
- To understand the mechanisms underlying age-related immunotherapy efficacy.
- To identify potential strategies to overcome immunotherapy resistance in elderly patients.
Main Methods:
- Flow cytometry to analyze immune cell infiltration in the tumor microenvironment (TME).
- In vivo assays for T cell proliferation, cytotoxicity, and migration.
- Quantitative PCR for gene expression analysis (IFN-γ, NK-associated chemokine).
- Adoptive transfer of NK cells from young to aged mice.
Main Results:
- Elderly patients (≥75 years) with advanced non-small cell lung cancer (aNSCLC) showed reduced progression-free survival (PFS), overall survival (OS), and clinical response to immunotherapy.
- Aged mice exhibited significantly reduced NK cell infiltration in the TME compared to younger mice.
- Aged NK cells suppressed CD8+ T cell activation by inhibiting CD103+ dendritic cell (DC) recruitment and activation.
- Adoptive transfer of young NK cells reversed immunotherapy resistance in aged mice by remodeling the TME.
Conclusions:
- Elderly patients and aged mice demonstrate decreased sensitivity to immunotherapy.
- Reduced NK cell numbers in aged mice contribute to immunotherapy resistance.
- This resistance is mediated by impaired CD103+ DC recruitment and reduced CD86 expression, ultimately hindering anti-tumor immunity.
