{"doi":"10.1136/jitc-2023-006991","title":"Cell membrane-anchored and tumor-targeted IL-12 T-cell therapy destroys cancer-associated fibroblasts and disrupts extracellular matrix in heterogenous osteosarcoma xenograft models","abstract":"Background The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted chimeric antigen receptor-T cell therapy cannot infiltrate ECM-rich tumors such as osteosarcoma. Method In this study, we used RNA sequencing to assess whether the recently invented membrane-anchored and tumor-targeted IL-12-armed (attIL12) T cells, which bind cell-surface vimentin (CSV) on tumor cells, could destroy CAFs to disrupt the ECM. We established an in vitro model of the interaction between osteosarcoma CAFs and attIL12-T cells to uncover the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors. Results RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment, and CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL-12-targeted or tumor-targeted IL-12-T cells, did not disrupt the ECM because this effect depended on the engagement between CSV on the tumor cell and its ligand on the attIL12-T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production on interacting with CSV + tumor cells, suppressing transforming growth factor beta secretion and in turn upregulating FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T-cell infiltration and tumor inhibition. Conclusions This study unveiled a novel therapy—attIL12-T cells—for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma.","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":419999,"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":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"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":13708,"name":"Alexander J. Lazar","orcid":"0000-0002-6395-4499","position":1,"is_corresponding":false},{"id":309158,"name":"Davis R. Ingram","orcid":"0000-0001-5967-1501","position":2,"is_corresponding":false},{"id":105064,"name":"Wei‐Lien Wang","orcid":"0000-0001-8809-4424","position":3,"is_corresponding":false},{"id":861898,"name":"Wendong Zhang","orcid":"0000-0003-1762-9246","position":4,"is_corresponding":false},{"id":350397,"name":"Zhiliang Jia","orcid":"0000-0003-2690-1512","position":5,"is_corresponding":false},{"id":736302,"name":"Dristhi Ragoonanan","orcid":"0000-0002-8199-9404","position":6,"is_corresponding":false},{"id":628616,"name":"Jian Wang","orcid":"0000-0001-7104-0673","position":7,"is_corresponding":false},{"id":453831,"name":"Xueqing Xia","orcid":null,"position":8,"is_corresponding":false},{"id":746066,"name":"Kris M. Mahadeo","orcid":"0000-0003-2649-9674","position":9,"is_corresponding":false},{"id":398284,"name":"Richard Görlick","orcid":"0000-0001-8995-2929","position":10,"is_corresponding":false},{"id":271523,"name":"Shulin Li","orcid":"0000-0001-5657-4183","position":11,"is_corresponding":false},{"id":90488,"name":"Jiemiao Hu","orcid":"0000-0002-5142-0641","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T01:57:19.937291Z","pmid":"38199607","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":[]}