(458) Overexpression of FGF21 in thymic stromal cells enhances T cell responses to viral infection and immune checkpoint inhibition efficacy during aging

Introduction/Rationale: Age-associated thymus atrophy diminishes T cell repertoire diversity, diminishing responsiveness to vaccination, viral infection, and tumor surveillance. Age-associated T cell dysregulation includes the persistence of virus-specific lung tissue resident memory T (Trm) cells in aged mice after influenza infection, driving chronic non-resolving inflammation and lung pathology 60 days post-infection (d.p.i.) Our recent work demonstrated that sustained thymic overexpression of fibroblast growth factor 21 (FGF21) in LPOFGF21 knock-in (KI) mice promotes increased thymic size and naïve T cell export in aged mice, improving age-related declines in CD8+ T cell responses to influenza in the acute phase, at 10 d.p.i.

Methods: To further test the impact of thymic overexpression of FGF21 on lung Trm and pathology in older mice, we examined immune responses to primary and heterosubtypic secondary challenge in 12–15-month-old LPOWT and LPOFGF21 mice at 7 and 60 d.p.i. Mice were infected intranasally with IAV PR8 only, or with IAV PR8 20 days after primary IAV X31 infection, and were analyzed at 7 or 60 d.p.i.

Results: Sustained FGF21 overexpression in LPOFGF21 mice mitigated the age-associated accumulation of CD8+ Trm, and the associated chronic lung pathology at 60 d.p.i. It also increased the frequency of T follicular helper and class-switched B cells in mediastinal lymph node at 7 and 60 d.p.i. We also tested the efficacy of immune checkpoint inhibition (ICI, anti-PD-L1 antibody) treatment in young and aged LPOFGF21 KI mice and age-matched controls using a B16 melanoma tumor model. We found that aging impaired tumor control and ICI efficacy in aged control mice, and that these age-associated impairments were ameliorated in age-matched LPOFGF21 KI mice.

Conclusion: These results suggest that intrathymic FGF21 overexpression mitigates age-associated declines in anti-viral and anti-tumor CD8+ T cell responses, revealing a potential therapeutic target for improving T cell function in aging.