{"doi":"10.1136/jitc-2022-006649","title":"Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia","abstract":"Background Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown. Methods Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL. Results We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYC high human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15. Conclusion We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":341111,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":663969,"name":"Adeleh Taghi Khani","orcid":null,"position":1,"is_corresponding":false},{"id":574672,"name":"Caroline Duault","orcid":"0000-0003-2742-1668","position":2,"is_corresponding":false},{"id":1077169,"name":"Soraya Aramburo","orcid":null,"position":3,"is_corresponding":false},{"id":842923,"name":"Ashly Sanchez Ortiz","orcid":null,"position":4,"is_corresponding":false},{"id":662949,"name":"Sung June Lee","orcid":"0000-0002-0627-5393","position":5,"is_corresponding":false},{"id":680197,"name":"Anthony Chan","orcid":"0000-0002-7091-1294","position":6,"is_corresponding":false},{"id":290594,"name":"Tinisha McDonald","orcid":null,"position":7,"is_corresponding":false},{"id":397396,"name":"Min Huang","orcid":"0000-0002-0771-1994","position":8,"is_corresponding":false},{"id":106442,"name":"Norman J. Lacayo","orcid":"0000-0003-4573-5118","position":9,"is_corresponding":false},{"id":397400,"name":"Kathleen M. Sakamoto","orcid":"0000-0003-0494-8838","position":10,"is_corresponding":false},{"id":253516,"name":"Jianhua Yu","orcid":"0000-0002-0326-3223","position":11,"is_corresponding":false},{"id":323028,"name":"Christian Hurtz","orcid":"0000-0001-8346-190X","position":12,"is_corresponding":false},{"id":318325,"name":"Martin Carroll","orcid":"0000-0002-5622-3735","position":13,"is_corresponding":false},{"id":273631,"name":"Sarah K. Tasian","orcid":"0000-0003-1327-1662","position":14,"is_corresponding":false},{"id":289773,"name":"Lucy Ghoda","orcid":"0000-0002-8212-3586","position":15,"is_corresponding":false},{"id":108574,"name":"Guido Marcucci","orcid":"0000-0002-3983-5908","position":16,"is_corresponding":false},{"id":253485,"name":"Zhaohui Gu","orcid":"0000-0003-1581-1327","position":17,"is_corresponding":false},{"id":226996,"name":"Steven T. Rosen","orcid":"0000-0002-8818-7724","position":18,"is_corresponding":false},{"id":401865,"name":"Saro H. Armenian","orcid":"0000-0003-2604-8603","position":19,"is_corresponding":false},{"id":569887,"name":"Shai Izraeli","orcid":"0000-0002-6938-2540","position":20,"is_corresponding":false},{"id":230599,"name":"Chun‐Wei Chen","orcid":"0000-0002-8737-6830","position":21,"is_corresponding":false},{"id":3645,"name":"Michael A. Caligiuri","orcid":"0000-0002-4095-3020","position":22,"is_corresponding":false},{"id":249979,"name":"Stephen J. Forman","orcid":"0000-0002-2803-4152","position":23,"is_corresponding":false},{"id":3342,"name":"Holden T. 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