{"doi":"10.1101/2020.02.07.939199","title":"Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4 <sup>+</sup> T cell-dependent manner","abstract":"Abstract Pancreatic ductal adenocarcinoma (PDAC) is exceptionally resistant to immune checkpoint inhibition (ICI). We previously reported that elevated systemic interleukin-6 (IL-6) and increased numbers of T cells positive for circulating cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) correlate with worse overall survival in patients with PDAC. We postulated that combined blockade of IL-6 and CTLA-4 would significantly enhance anti-tumor immune responses to PDAC. Dual blockade of IL-6 and CTLA-4 in immune competent mice bearing subcutaneously injected pancreatic tumors significantly inhibited tumor growth, accompanied by overwhelming T cell infiltration. Therapeutic efficacy was confirmed in an orthotopic murine model of pancreatic cancer and T cell depletion studies unveiled a unique dependence on CD4 + T cells for anti-tumor activity of dual IL-6 and CTLA-4 blockade. In vitro studies utilizing T cells from a TRP-1 transgenic mouse as an antigen-specific model system demonstrate this combination therapy elicits increased IFN-γ production by activated CD4 + T cells. Additionally, IFN-γ stimulation of pancreatic tumor cells in vitro profoundly increased tumor cell production of CXCR3 specific chemokines (CXCL10 and CXCL9). Further studies blocking CXCR3 in the presence of combined IL-6 and CTLA-4 blockade prevented orthotopic tumor regression, demonstrating a dependence on the CXCR3 axis for anti-tumor efficacy. We also found combination therapy increased intratumoral CD4 + T cells and elicited systemic changes in T-helper subsets. These data represent the first report of IL-6 and CTLA-4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy. Given these results, this therapeutic combination has potential for immediate clinical translation. One Sentence Summary Blockade of interleukin-6 in pancreatic cancer enhances CTLA-4 immune checkpoint inhibition to regress tumors in a CD4 + T cell and CXCR3-dependent manner.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123276,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9669,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":566638,"name":"Christopher McQuinn","orcid":null,"position":1,"is_corresponding":false},{"id":354297,"name":"Mohammad Y. Zaidi","orcid":"0000-0002-4246-1724","position":2,"is_corresponding":false},{"id":314034,"name":"Hannah M. Knochelmann","orcid":"0000-0003-0644-123X","position":3,"is_corresponding":false},{"id":451407,"name":"Thomas A. Mace","orcid":"0000-0003-1070-6819","position":4,"is_corresponding":false},{"id":254870,"name":"Zhengjia Chen","orcid":"0000-0002-6301-4931","position":5,"is_corresponding":false},{"id":566098,"name":"Chao Zhang","orcid":"0000-0003-2776-5647","position":6,"is_corresponding":false},{"id":354299,"name":"Matthew R. Farren","orcid":"0000-0001-5510-8869","position":7,"is_corresponding":false},{"id":355024,"name":"Amanda N. Ruggieri","orcid":null,"position":8,"is_corresponding":false},{"id":478704,"name":"Jacob S. Bowers","orcid":"0000-0003-2589-2351","position":9,"is_corresponding":false},{"id":566639,"name":"Reena Shakya","orcid":null,"position":10,"is_corresponding":false},{"id":276858,"name":"Alton B. Farris","orcid":"0000-0001-5534-7763","position":11,"is_corresponding":false},{"id":451409,"name":"Gregory Young","orcid":"0000-0001-9886-6205","position":12,"is_corresponding":false},{"id":417798,"name":"William E. Carson","orcid":"0000-0001-7024-7533","position":13,"is_corresponding":false},{"id":354302,"name":"Bassel F. El‐Rayes","orcid":"0000-0002-2661-5746","position":14,"is_corresponding":false},{"id":314041,"name":"Chrystal M. Paulos","orcid":"0000-0002-0784-2601","position":15,"is_corresponding":false},{"id":328027,"name":"Gregory B. Lesinski","orcid":"0000-0002-8787-7678","position":16,"is_corresponding":false},{"id":354296,"name":"Michael B. Ware","orcid":"0000-0002-6139-1952","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:14:59.547352Z","pmid":null,"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":[]}