HuR–SerpinB9 Axis Regulates Tumor T-Cell Fitness and Persistence via Post-Transcriptional Control

Introduction/Rationale: Post-transcriptional regulation (PTR) plays a crucial role in shaping T-cell gene expression programs that adapt to their microenvironment. Among RNA-binding proteins (RBPs) involved in PTR, Human antigen R (HuR; ELAVL1) binds to AU-rich elements within mRNAs encoding regulators of proliferation, inflammation, and immune responses. While HuR controls cytokine expression and T-cell development, its role in effector function and persistence remains unclear.

Methods: We utilized a T cell–specific HuR knockout (HuRfl/fl CD4-Cre) mouse model and employed flow cytometry, RIP-seq, and transcriptomic profiling to identify HuR-bound targets and their downstream effects. Functional analyses included chronic stimulation followed by characterization, ELISA, HuR and SerpinB9 overexpression, adoptive transfer into Rag ko mice (colitis), and the B16-F10 tumor model to assess T-cell function and persistence.

Results: Using this approach, we found that HuR-deficient T cells exhibit increased effector cytokine secretion, decreased CD27 expression, elevated KLRG1 levels, and enhanced SA-β-Gal activity, characteristics of replicative senescence. Adoptive transfer of HuR-deficient T cells caused less severe colitis in Rag KO mice despite their effector phenotype, suggesting impaired persistence. Corroborating these findings, HuR expression was significantly reduced in tumor-infiltrating and aged T cells. Conversely, HuR overexpression decreased senescence and restored memory marker expression in both mouse and human aged T cells and TILs. Mechanistically, HuR bound transcripts involved in immune regulation, including SerpinB9, a granzyme B inhibitor vital for cytotoxic T-cell survival. Overexpressing SerpinB9 in wild-type and HuR-deficient T cells enhanced persistence under chronic stimulation and improved tumor control.

Conclusion: These findings highlight a HuR-SerpinB9 axis that regulates T-cell senescence and persistence, offering a potential therapeutic target in cancer and autoimmune diseases.