{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:58:48Z","timestamp":1792166328561,"version":"4.4.0"},"reference-count":50,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T00:00:00Z","timestamp":1589932800000},"content-version":"unspecified","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although immune checkpoint inhibitors have revolutionized cancer treatment, clinical benefit with this class of agents has been limited to a subset of patients. Hence, more effective means to target tumor cells that express immune checkpoint molecules should be developed. For the first time, we report a novel natural killer (NK) cell line, programmed death-ligand 1 (PD-L1) targeting high-affinity natural killer (t-haNK), which was derived from NK-92 and was engineered to express high-affinity CD16, endoplasmic reticulum-retained interleukin (IL)-2, and a PD-L1-specific chimeric antigen receptor (CAR). We show that PD-L1 t-haNK cells also retained the expression of native NK receptors and carried a high content of granzyme and perforin granules.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      NanoString, flow cytometry, and immunofluorescence analyses were performed to characterize the phenotype of irradiated PD-L1 t-haNK cells. In vitro PD-L1 t-haNK cell activity against cancer cell lines and human peripheral blood mononuclear cells (PBMCs) was determined via flow-based and\n                      <jats:sup>111<\/jats:sup>\n                      In-release killing assays. The antitumor effect of PD-L1 t-haNK cells in vivo was investigated using MDA-MB-231, H460, and HTB1 xenograft models in NOD-scid IL2Rgamma\n                      <jats:sup>null<\/jats:sup>\n                      (NSG) mice. Additionally, the antitumor effect of PD-L1 t-haNK cells, in combination with anti-PD-1 and N-803, an IL-15 superagonist, was evaluated using mouse oral cancer 1 syngeneic model in C57BL\/6 mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We show that PD-L1 t-haNK cells expressed PD-L1-targeting CAR and CD16, retained the expression of native NK receptors, and carried a high content of granzyme and perforin granules. In vitro, we demonstrate the ability of irradiated PD-L1 t-haNK cells to lyse 20 of the 20 human cancer cell lines tested, including triple negative breast cancer (TNBC) and lung, urogenital, and gastric cancer cells. The cytotoxicity of PD-L1 t-haNK cells was correlated to the PD-L1 expression of the tumor targets and can be improved by pretreating the targets with interferon (IFN)-\u03b3. In vivo, irradiated PD-L1 t-haNK cells inhibited the growth of engrafted TNBC and lung and bladder tumors in NSG mice. The combination of PD-L1 t-haNK cells with N-803 and anti-PD-1 antibody resulted in superior tumor growth control of engrafted oral cavity squamous carcinoma tumors in C57BL\/6 mice. In addition, when cocultured with human PBMCs, PD-L1 t-haNK cells preferentially lysed the myeloid-derived suppressor cell population but not other immune cell types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These studies demonstrate the antitumor efficacy of PD-L1 t-haNK cells and provide a rationale for the potential use of these cells in clinical studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2019-000450","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T06:04:45Z","timestamp":1590041085000},"page":"e000450","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":147,"title":["PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations"],"prefix":"10.1136","volume":"8","clinical-trial-number":[{"clinical-trial-number":"nct00001846","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct00514072","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Kellsye P","family":"Fabian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle R","family":"Padget","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee N.","family":"Donahue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Solocinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvette","family":"Robbins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clint T.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahrooz","family":"Rabizadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Soon-Shiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7932-4072","authenticated-orcid":false,"given":"Jeffrey","family":"Schlom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5282-3154","authenticated-orcid":false,"given":"James W","family":"Hodge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,5,20]]},"reference":[{"key":"2020061616125166000_8.1.e000450.1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-015-1761-x"},{"key":"2020061616125166000_8.1.e000450.2","article-title":"Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells","volume":"8","author":"Gong","year":"1994","journal-title":"Leukemia"},{"key":"2020061616125166000_8.1.e000450.3","first-page":"2859-68","article-title":"Antileukemia activity of a natural killer cell line against human leukemias","volume":"4","author":"Yan","year":"1998","journal-title":"Clin Cancer Res"},{"key":"2020061616125166000_8.1.e000450.4","doi-asserted-by":"publisher","DOI":"10.1089\/106161299320316"},{"key":"2020061616125166000_8.1.e000450.5","doi-asserted-by":"publisher","DOI":"10.1089\/152581601750288975"},{"key":"2020061616125166000_8.1.e000450.6","doi-asserted-by":"publisher","DOI":"10.1080\/14653240802301872"},{"key":"2020061616125166000_8.1.e000450.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2013.06.017"},{"key":"2020061616125166000_8.1.e000450.8","doi-asserted-by":"crossref","unstructured":"Williams BA , Law AD , Routy B , et al . 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