{"doi":"10.1073/pnas.1914906117","title":"Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites","abstract":"Robust cytotoxic T cell infiltration has proven to be difficult to achieve in solid tumors. We set out to develop a flexible protocol to efficiently transfect tumor and stromal cells to produce immune-activating cytokines, and thus enhance T cell infiltration while debulking tumor mass. By combining ultrasound with tumor-targeted microbubbles, membrane pores are created and facilitate a controllable and local transfection. Here, we applied a substantially lower transmission frequency (250 kHz) than applied previously. The resulting microbubble oscillation was significantly enhanced, reaching an effective expansion ratio of 35 for a peak negative pressure of 500 kPa in vitro. Combining low-frequency ultrasound with tumor-targeted microbubbles and a DNA plasmid construct, 20% of tumor cells remained viable, and ∼20% of these remaining cells were transfected with a reporter gene both in vitro and in vivo. The majority of cells transfected in vivo were mucin 1 + /CD45 − tumor cells. Tumor and stromal cells were then transfected with plasmid DNA encoding IFN-β, producing 150 pg/10 6 cells in vitro, a 150-fold increase compared to no-ultrasound or no-plasmid controls and a 50-fold increase compared to treatment with targeted microbubbles and ultrasound (without IFN-β). This enhancement in secretion exceeds previously reported fourfold to fivefold increases with other in vitro treatments. Combined with intraperitoneal administration of checkpoint inhibition, a single application of IFN-β plasmid transfection reduced tumor growth in vivo and recruited efficacious immune cells at both the local and distant tumor sites.","journal":"Proceedings of the National Academy of Sciences","year":2020,"id":55428,"datarank":2.471246903771807,"base_score":4.543294782270004,"endowment":4.543294782270004,"self_citation_contribution":0.6814942173405006,"citation_network_contribution":1.7897526864313063,"self_endowment_contribution":0.6814942173405006,"citer_contribution":1.7897526864313063,"corpus_percentile":null,"corpus_rank":null,"citation_count":93,"citer_count":71,"citers_with_citation_signal":62,"citers_with_endowment":62,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.12214364.v2"]},"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":286454,"name":"Yi Feng","orcid":"0000-0002-9489-4812","position":1,"is_corresponding":false},{"id":286455,"name":"Josquin Foiret","orcid":"0000-0002-7946-8161","position":2,"is_corresponding":false},{"id":286456,"name":"Azadeh Kheirolomoom","orcid":"0000-0002-2173-4893","position":3,"is_corresponding":false},{"id":286457,"name":"Hua Zhang","orcid":"0000-0002-4700-5971","position":4,"is_corresponding":false},{"id":286458,"name":"Elizabeth S. 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