The Phosphatase DUSP2 Constrains Lymphoid Remodeling and Immunotherapy Response in Lung Squamous Carcinoma - PubMed
3 hours ago
- #tumor microenvironment
- #immunotherapy resistance
- #lung squamous carcinoma
- In lung squamous cell carcinoma (LUSC), immune checkpoint blockade (ICB) responders show expansion of B cells and T follicular helper (Tfh) cells, supporting tertiary lymphoid structure (TLS) formation.
- Non-responders to ICB exhibit persistent IFN-I signaling from CD36+SPP1+ tumor-associated macrophages, disrupting lymphoid organization and promoting T cell dysfunction via aberrant NFAT signaling.
- IFN-I induces phosphatase DUSP2 expression in pre-exhausted T cells, leading to NFAT dephosphorylation and nuclear accumulation, which upregulates inhibitory receptors and impairs Tfh differentiation.
- Genetic ablation of Dusp2 restores CD8+ T cell function and Tfh-B cell interactions, enhancing ICB responsiveness, identifying the IFN-I-DUSP2-NFAT axis as a key limiter of immunotherapy efficacy in LUSC.