{"doi":"10.1101/2024.09.26.615308","title":"Interleukin 6 drives durable T cell-mediated immunity to pancreatic cancer","abstract":"ABSTRACT Background & Aims: Tumor immune resistance is recognized as a contributor to low survivorship in pancreatic ductal adenocarcinoma (PDAC). The inflammatory cytokine interleukin-6 (IL-6) promotes polarization of CD4 T cell populations away from immune tolerance, and induces differentiation of cytotoxic CD8 T cells. This work aims to test whether IL-6 could stimulate an anti-tumor response in PDAC Methods: We overexpressed IL-6 in multiple Kras G12D/+ , Tp53 R172H/+, Pdx1-Cre (KPC) cell lines, which were orthotopically implanted in mice (OT-PDAC IL6 ). We followed mouse survival and measured tumor growth, tumor histology, and plasma IL-6 at 5 and 10 days after tumor implantation. We measured tumor immune cell infiltration via flow cytometry and histology. We used antibody-based T cell depletion and secondary tumor implantation rechallenge to test the dependency of the durable immune reaction on T cells. We use lipid nanoparticle (LNP)-based delivery of IL-6 mRNA to the pancreas as an orthogonal approach for testing the effect of elevated IL-6 in the tumor microenvironment on anti-tumor T cell invasion. Results: Improved survival occurred in all instances of OT-PDAC IL6 , with one cell line (KxPxCx) reproducibly resulting in long-term recurrence-free survival. With KxPxCx cells, circulating IL-6 was 100-fold higher in OT-KxPxCx IL6 than in OT-KxPxCx parental mice. Flow cytometry revealed increased T cells and NK cells, and decreased T regulatory cells, and we observed significantly increased lymphoid aggregates in OT-KXPXCX IL6 as compared to OT--KxPxCx parental tumors. Antibody-based CD4 + and CD8 + T cell depletion prevented tumor clearance and completely abolished the survival advantage in OT-KxPxCx IL6 mice. The anti-tumor immune response to OT-KxPxCx IL6 rendered mice immune to re-challenge with OT-KxPxCx parental tumors. LNP delivery of IL-6 to the pancreas elevated systemic IL-6 levels ∼50 fold, lowered tumor burden, and increased anti-tumor T cell phenotypes. Conclusions: Locally high IL-6 concentrations potently enhance the T cell-mediated anti-tumor response to PDAC. SYNOPSIS: Interleukin-6 induces rapid and durable T cell-driven immune clearance of pancreatic ductal adenocarcinoma. The anti-tumor immune microenvironment is hallmarked by increased lymphoid aggregate formation, increased CD4 T cell abundance, and decreased Treg abundance.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":491983,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":72272,"name":"Alexandra Q. Bartlett","orcid":"0000-0001-7912-6084","position":1,"is_corresponding":false},{"id":633477,"name":"Heike Mendez","orcid":null,"position":2,"is_corresponding":false},{"id":325375,"name":"Xinxia Zhu","orcid":"0009-0009-4041-1561","position":3,"is_corresponding":false},{"id":633475,"name":"Peter R. Levasseur","orcid":null,"position":4,"is_corresponding":false},{"id":1117248,"name":"Parham Diba","orcid":"0000-0003-1014-510X","position":5,"is_corresponding":false},{"id":1338293,"name":"Namratha Turuvekere Vittala Murthy","orcid":null,"position":6,"is_corresponding":false},{"id":1338294,"name":"Jessica Dickie","orcid":null,"position":7,"is_corresponding":false},{"id":1337847,"name":"Matthew R. McWhorter","orcid":"0000-0002-6401-7325","position":8,"is_corresponding":false},{"id":1338295,"name":"Antony Jozic","orcid":null,"position":9,"is_corresponding":false},{"id":504514,"name":"Yulia Eygeris","orcid":"0000-0002-8927-5128","position":10,"is_corresponding":false},{"id":249765,"name":"Gaurav Sahay","orcid":"0000-0003-1071-0500","position":11,"is_corresponding":false},{"id":105484,"name":"Katelyn T. Byrne","orcid":"0000-0002-2459-9041","position":12,"is_corresponding":false},{"id":674332,"name":"Gregory D. Scott","orcid":"0000-0003-0830-5557","position":13,"is_corresponding":false},{"id":255931,"name":"Robert Eil","orcid":"0000-0003-3030-9327","position":14,"is_corresponding":false},{"id":632208,"name":"Aaron J. Grossberg","orcid":"0000-0003-4690-4948","position":15,"is_corresponding":false},{"id":342408,"name":"Paige C. Arneson‐Wissink","orcid":"0000-0002-2706-9652","position":0,"is_corresponding":true}],"reference_count":20,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:49.768795Z","pmid":"39386578","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}