{"doi":"10.1101/2022.09.20.508732","title":"T cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL-1 and TNFα Inflammation","abstract":"Abstract Resistance to immune checkpoint inhibitors (ICIs) is common, even in tumors with T cell infiltration. We thus investigated consequences of ICI-induced T cell infiltration in the microenvironment of resistant tumors. T cells increased in ICI-resistant tumors following treatment as did neutrophils, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL-1 Receptor 1 (IL1R1), enabling a synergistic response to IL-1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting neutrophils. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNFα both in vitro and in vivo . Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a novel mechanism of ICI resistance, wherein treatment-induced T cell activity can drive resistance in tumors responsive to IL-1 and TNFα, with important therapeutic implications. Statement of Significance Although T cell-infiltrated cancers are frequently resistant to immune checkpoint inhibitor therapies, mechanisms of resistance beyond T cell exhaustion remain unclear. Here, we reveal the functional significance of tumor- infiltrating T cells in resistant tumors, which surprisingly instruct immunosuppressive inflammation in mouse and human cancers responsive to IL-1 and TNFα.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":301890,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":993365,"name":"Sophia M. Guldberg","orcid":"0000-0002-0102-4341","position":1,"is_corresponding":false},{"id":252117,"name":"Barzin Y. Nabet","orcid":"0000-0002-4824-3533","position":2,"is_corresponding":false},{"id":993876,"name":"Jie Zeng Yu","orcid":null,"position":3,"is_corresponding":false},{"id":993366,"name":"Eun Ji Kim","orcid":"0000-0001-9305-4769","position":4,"is_corresponding":false},{"id":232879,"name":"Kamir J. Hiam-Galvez","orcid":"0000-0002-1956-0257","position":5,"is_corresponding":false},{"id":751109,"name":"Jacqueline L. Yee","orcid":"0000-0001-7860-2237","position":6,"is_corresponding":false},{"id":232882,"name":"Rachel DeBarge","orcid":"0000-0001-9223-1364","position":7,"is_corresponding":false},{"id":232883,"name":"Iliana Tenvooren","orcid":"0000-0002-9833-7669","position":8,"is_corresponding":false},{"id":993367,"name":"Naa Asheley Ashitey","orcid":"0009-0008-4154-4158","position":9,"is_corresponding":false},{"id":429741,"name":"Filipa Lynce","orcid":"0000-0001-6615-7076","position":10,"is_corresponding":false},{"id":74572,"name":"Deborah Dillon","orcid":"0000-0002-4977-6673","position":11,"is_corresponding":false},{"id":95403,"name":"Jennifer M. Rosenbluth","orcid":"0000-0003-1314-6976","position":12,"is_corresponding":false},{"id":15988,"name":"Matthew H. Spitzer","orcid":"0000-0002-5291-3819","position":13,"is_corresponding":false},{"id":232885,"name":"Nam Woo Cho","orcid":"0000-0002-5785-9698","position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":null,"created_at":"2026-07-19T00:32:06.309890Z","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":[]}