1250 Post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma
Year: 2025
Type: conference-abstract
Abstract: The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by the restrained function of effector T cells that drive resistance to immunotherapy. Although tumor-extrinsic stroma and myeloid cells have been shown to mediate PDAC immune evasion, the role of tumor-intrinsic posttranscriptional gene regulation in driving tumor–immune cross-talk has been relatively unexplored. In this study, we report that the RNA-binding protein human antigen R (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 affecting 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 relevance. Overall, we found that the posttranscriptional regulator HuR facilitates immune evasion in PDAC by constraining T-cell function, identifying HuR blockade as a promising therapeutic strategy in combination with immunotherapies.
Authors: Yifei Guo, Jennifer M. Finan, Alexandra Q. Bartlett, Katherine R. Pelz, Shamilene Sivagnanam, Katie E. Blise, Nell Kirchberger, Konjit Betre, Yuhui Wei, Jennifer R. Eng, Vidhi M. Shah, Koei Chin, Grace A. McCarthy, Hen Halamish, Kevin MacPherson-Hawthorne, Colin J. Daniel, Canping Chen, Aaron J. Grossberg, Zheng Xia, Sha Cao, Lisa M. Coussens, Rosalie C. Sears, Jonathan R. Brody, Robert Eil
Institution: Oregon Health & Science University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4415899241
Cites:
Cited by:
Related to: