The post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma
Menée in vitro et à l'aide de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel le régulateur post-transcriptionnel HuR favorise l'échappement immunitaire en stabilisant les transcrits de la voie de signalisation de la kinase mTOR, ce qui modifie le métabolisme tumoral puis altère la fonction des lymphocytes et leur nombre en les privant de nutriments
The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by restrained function of effector T cells that drives resistance to immunotherapy. While tumor-extrinsic stroma and myeloid cells have been shown to mediate PDAC immune evasion, the role of tumor-intrinsic post-transcriptional gene regulation in driving tumor–immune crosstalk has been relatively unexplored. Here, we report that the RNA-binding protein HuR (ELAVL1) is enriched in human PDAC and negatively correlates with T-cell infiltration. In two immunocompetent, murine models of PDAC, we found that genetic disruption of HuR impaired tumor growth without significantly impacting in vivo proliferation. Comprehensive spatial and flow cytometry profiling of the PDAC TME revealed that genetic disruption of HuR in PDAC enhanced both T-cell number and functional state. Moreover, T-cell depletion abrogated the growth difference caused by HuR loss. Mechanistically, RNA immunoprecipitation sequencing, single-cell RNA sequencing, and orthogonal functional assays in vitro and in vivo showed that HuR stabilized mTOR pathway transcripts critical for metabolic adaptation in PDAC. HuR-driven metabolic reprogramming promoted tumor nutrient dominance and limited nutrient consumption by neighboring tumor-reactive T cells. Accordingly, HuR depletion sensitized PDAC tumors to immune checkpoint blockade and allowed for the expansion of tumor-specific T-cell populations, suggesting that HuR-mediated nutrient dominance and immune evasion have translational relevancy. Overall, we found that the post-transcriptional regulator HuR facilitates immune evasion in PDAC by constraining T-cell function, identifying HuR blockade as a promising therapeutic strategy in combination with immunotherapies.
Cancer Immunology Research , résumé, 2026