{"doi":"10.4049/jimmunol.2000926","title":"Retargeting IL-2 Signaling to NKG2D-Expressing Tumor-Infiltrating Leukocytes Improves Adoptive Transfer Immunotherapy","abstract":"Abstract Ex vivo expansion followed by reinfusion of tumor-infiltrating leukocytes (TILs) has been used successfully for the treatment of multiple malignancies. Most protocols rely on the use of the cytokine IL-2 to expand TILs prior to reinfusion. In addition, TIL administration relies on systemic administration of IL-2 after reinfusion to support transferred cell survival. The use of IL-2, however, can be problematic because of its preferential expansion of regulatory T and myeloid cells as well as its systemic side effects. In this study, we describe the use of a novel IL-2 mutant retargeted to NKG2D rather than the high-affinity IL-2R for TIL-mediated immunotherapy in a murine model of malignant melanoma. We demonstrate that the NKG2D-retargeted IL-2 (called OMCPmutIL-2) preferentially expands TIL-resident CTLs, such as CD8+ T cells, NK cells, and γδT cells, whereas wild-type IL-2 provides a growth advantage for CD4+Foxp3+ T cells as well as myeloid cells. OMCPmutIL-2–expanded CTLs express higher levels of tumor-homing receptors, such as LFA-1, CD49a, and CXCR3, which correlate with TIL localization to the tumor bed after i.v. injection. Consistent with this, OMCPmutIL-2–expanded TILs provided superior tumor control compared with those expanded in wild-type IL-2. Our data demonstrate that adoptive transfer immunotherapy can be improved by rational retargeting of cytokine signaling to NKG2D-expressing CTLs rather than indiscriminate expansion of all TILs.","journal":"The Journal of Immunology","year":2021,"id":198469,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":773649,"name":"Dongge Li","orcid":"0000-0001-7205-353X","position":1,"is_corresponding":false},{"id":773650,"name":"Yizhan Guo","orcid":"0000-0001-7627-6423","position":2,"is_corresponding":false},{"id":773651,"name":"Bayan Mahgoub","orcid":"0000-0001-5677-8784","position":3,"is_corresponding":false},{"id":774318,"name":"Lea Paragas","orcid":null,"position":4,"is_corresponding":false},{"id":773652,"name":"Jacqueline S. Slobin","orcid":"0000-0001-6171-0610","position":5,"is_corresponding":false},{"id":773653,"name":"Zhongcheng Mei","orcid":"0000-0003-0602-839X","position":6,"is_corresponding":false},{"id":75843,"name":"Amir Manafi","orcid":"0000-0002-9274-9128","position":7,"is_corresponding":false},{"id":773654,"name":"Atsushi Hata","orcid":"0000-0002-9578-683X","position":8,"is_corresponding":false},{"id":244485,"name":"Kang Li","orcid":"0009-0007-6642-3259","position":9,"is_corresponding":false},{"id":773655,"name":"Lei Shi","orcid":"0000-0002-6510-7904","position":10,"is_corresponding":false},{"id":579161,"name":"John Westwick","orcid":null,"position":11,"is_corresponding":false},{"id":79696,"name":"Craig L. Slingluff","orcid":"0000-0002-6664-4373","position":12,"is_corresponding":false},{"id":608980,"name":"Eric Lazear","orcid":"0000-0001-6173-8904","position":13,"is_corresponding":false},{"id":267156,"name":"Alexander S. Krupnick","orcid":"0000-0002-1790-6197","position":14,"is_corresponding":false},{"id":773648,"name":"Anirban Banerjee","orcid":"0000-0001-7678-1868","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:50:31.857233Z","pmid":"34155069","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":[]}