{"doi":"10.1136/jitc-2020-001355","title":"Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas","abstract":"PURPOSE: Given the unmet need for novel immunotherapy in soft tissue sarcoma (STS), we sought to characterize the phenotype and function of intratumoral natural killer (NK) and T cells to identify novel strategies to augment tumor-infiltrating lymphocyte (TIL) function. EXPERIMENTAL DESIGN: Using prospectively collected specimens from dogs and humans with sarcomas, archived specimens, and The Cancer Genome Atlas (TCGA) data, we evaluated blood and tumor NK and T cell phenotype and function and correlated those with outcome. We then assessed the effects of interleukin 15 (IL-15) stimulation on both NK and T cell activation and TIGIT upregulation. Finally, we evaluated cytotoxic effects of IL-15 combined with TIGIT blockade using a novel anti-TIGIT antibody. RESULTS: TILs were strongly associated with survival outcome in both archived tissue and TCGA, but higher TIL content was also associated with higher TIGIT expression. Compared with blood, intratumoral NK and T cells showed significantly higher expression of both activation and exhaustion markers, in particular TIGIT. Ex vivo stimulation of blood and tumor NK and T cells from patients with STS with IL-15 further increased both activation and exhaustion markers, including TIGIT. Dogs with metastatic osteosarcoma receiving inhaled IL-15 also exhibited upregulation of activation markers and TIGIT. Ex vivo, combined IL-15 and TIGIT blockade using STS blood and tumor specimens significantly increased cytotoxicity against STS targets. CONCLUSION: Intratumoral NK and T cells are prognostic in STS, but their activation is marked by significant upregulation of TIGIT. Our data suggest that combined IL-15 and TIGIT blockade may be a promising clinical strategy in STS.","journal":"Journal for ImmunoTherapy of Cancer","year":2020,"id":55717,"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":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"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":265056,"name":"Morgan Darrow","orcid":null,"position":1,"is_corresponding":false},{"id":290327,"name":"Steve W Thorpe","orcid":null,"position":2,"is_corresponding":false},{"id":70323,"name":"Alicia A. Gingrich","orcid":"0000-0002-7239-0154","position":3,"is_corresponding":false},{"id":288707,"name":"Edmond F. O’Donnell","orcid":"0000-0001-9110-9981","position":4,"is_corresponding":false},{"id":288708,"name":"Alyssa Bellini","orcid":"0009-0008-0080-5251","position":5,"is_corresponding":false},{"id":262403,"name":"Ian R. Sturgill","orcid":"0000-0003-1869-6344","position":6,"is_corresponding":false},{"id":288709,"name":"Logan V. Vick","orcid":"0009-0006-9778-0120","position":7,"is_corresponding":false},{"id":262401,"name":"Cordelia Dunai","orcid":"0000-0001-5799-2387","position":8,"is_corresponding":false},{"id":262405,"name":"Kevin Stoffel","orcid":"0000-0003-1428-7471","position":9,"is_corresponding":false},{"id":288710,"name":"Yue Lyu","orcid":"0000-0002-6505-6422","position":10,"is_corresponding":false},{"id":30314,"name":"Shuai Chen","orcid":"0000-0002-9337-6191","position":11,"is_corresponding":false},{"id":288711,"name":"May Cho","orcid":"0000-0002-7152-0017","position":12,"is_corresponding":false},{"id":288712,"name":"Robert B. Rebhun","orcid":"0000-0002-8047-3494","position":13,"is_corresponding":false},{"id":259311,"name":"Arta M. Monjazeb","orcid":"0000-0001-5175-8004","position":14,"is_corresponding":false},{"id":259312,"name":"William J. Murphy","orcid":"0000-0002-2793-401X","position":15,"is_corresponding":false},{"id":262409,"name":"Robert J. Canter","orcid":"0000-0002-3331-5418","position":16,"is_corresponding":false},{"id":262400,"name":"Sean J. Judge","orcid":"0000-0002-1842-9468","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-18T21:05:29.672878Z","pmid":"33158916","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":[]}