Yekaterina Galat, Yuchen Du, Mariana Perepitchka, Xiao-Nan Li, Irina V Balyasnikova, William T Tse, Svetlana Dambaeva, Sylvia Schneiderman, Philip M Iannaccone, Oren Becher, Douglas K Graham, Vasiliy Galat
{"title":"体外血管分化系统有效地产生用于癌症免疫治疗的自然杀伤细胞。","authors":"Yekaterina Galat, Yuchen Du, Mariana Perepitchka, Xiao-Nan Li, Irina V Balyasnikova, William T Tse, Svetlana Dambaeva, Sylvia Schneiderman, Philip M Iannaccone, Oren Becher, Douglas K Graham, Vasiliy Galat","doi":"10.1080/2162402X.2023.2240670","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Immunotherapeutic innovation is crucial for limited operability tumors. CAR T-cell therapy displayed reduced efficiency against glioblastoma (GBM), likely due to mutations underlying disease progression. Natural Killer cells (NKs) detect cancer cells despite said mutations - demonstrating increased tumor elimination potential. We developed an NK differentiation system using human pluripotent stem cells (hPSCs). Via this system, genetic modifications targeting cancer treatment challenges can be introduced during pluripotency - enabling unlimited production of modified \"off-the-shelf\" hPSC-NKs.</p><p><strong>Methods: </strong>hPSCs were differentiated into hematopoietic progenitor cells (HPCs) and NKs using our novel organoid system. These cells were characterized using flow cytometric and bioinformatic analyses. HPC engraftment potential was assessed using NSG mice. NK cytotoxicity was validated using <i>in vitro</i> and <i>in vitro</i> K562 assays and further corroborated on lymphoma, diffuse intrinsic pontine glioma (DIPG), and GBM cell lines <i>in vitro</i>.</p><p><strong>Results: </strong>HPCs demonstrated engraftment in peripheral blood samples, and hPSC-NKs showcased morphology and functionality akin to same donor peripheral blood NKs (PB-NKs). The hPSC-NKs also displayed potential advantages regarding checkpoint inhibitor and metabolic gene expression, and demonstrated <i>in</i> <i>vitro</i> and <i>in</i> <i>vivo</i> cytotoxicity against various cancers.</p><p><strong>Conclusions: </strong>Our organoid system, designed to replicate <i>in</i> <i>vivo</i> cellular organization (including signaling gradients and shear stress conditions), offers a suitable environment for HPC and NK generation. The engraftable nature of HPCs and potent NK cytotoxicity against leukemia, lymphoma, DIPG, and GBM highlight the potential of this innovative system to serve as a valuable tool that will benefit cancer treatment and research - improving patient survival and quality of life.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2000,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/95/95/KONI_12_2240670.PMC10501168.pdf","citationCount":"0","resultStr":"{\"title\":\"In vitro vascular differentiation system efficiently produces natural killer cells for cancer immunotherapies.\",\"authors\":\"Yekaterina Galat, Yuchen Du, Mariana Perepitchka, Xiao-Nan Li, Irina V Balyasnikova, William T Tse, Svetlana Dambaeva, Sylvia Schneiderman, Philip M Iannaccone, Oren Becher, Douglas K Graham, Vasiliy Galat\",\"doi\":\"10.1080/2162402X.2023.2240670\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Immunotherapeutic innovation is crucial for limited operability tumors. CAR T-cell therapy displayed reduced efficiency against glioblastoma (GBM), likely due to mutations underlying disease progression. Natural Killer cells (NKs) detect cancer cells despite said mutations - demonstrating increased tumor elimination potential. We developed an NK differentiation system using human pluripotent stem cells (hPSCs). Via this system, genetic modifications targeting cancer treatment challenges can be introduced during pluripotency - enabling unlimited production of modified \\\"off-the-shelf\\\" hPSC-NKs.</p><p><strong>Methods: </strong>hPSCs were differentiated into hematopoietic progenitor cells (HPCs) and NKs using our novel organoid system. These cells were characterized using flow cytometric and bioinformatic analyses. HPC engraftment potential was assessed using NSG mice. NK cytotoxicity was validated using <i>in vitro</i> and <i>in vitro</i> K562 assays and further corroborated on lymphoma, diffuse intrinsic pontine glioma (DIPG), and GBM cell lines <i>in vitro</i>.</p><p><strong>Results: </strong>HPCs demonstrated engraftment in peripheral blood samples, and hPSC-NKs showcased morphology and functionality akin to same donor peripheral blood NKs (PB-NKs). The hPSC-NKs also displayed potential advantages regarding checkpoint inhibitor and metabolic gene expression, and demonstrated <i>in</i> <i>vitro</i> and <i>in</i> <i>vivo</i> cytotoxicity against various cancers.</p><p><strong>Conclusions: </strong>Our organoid system, designed to replicate <i>in</i> <i>vivo</i> cellular organization (including signaling gradients and shear stress conditions), offers a suitable environment for HPC and NK generation. The engraftable nature of HPCs and potent NK cytotoxicity against leukemia, lymphoma, DIPG, and GBM highlight the potential of this innovative system to serve as a valuable tool that will benefit cancer treatment and research - improving patient survival and quality of life.</p>\",\"PeriodicalId\":19683,\"journal\":{\"name\":\"Oncoimmunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.2000,\"publicationDate\":\"2023-09-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/95/95/KONI_12_2240670.PMC10501168.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Oncoimmunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/2162402X.2023.2240670\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Oncoimmunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/2162402X.2023.2240670","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
In vitro vascular differentiation system efficiently produces natural killer cells for cancer immunotherapies.
Background: Immunotherapeutic innovation is crucial for limited operability tumors. CAR T-cell therapy displayed reduced efficiency against glioblastoma (GBM), likely due to mutations underlying disease progression. Natural Killer cells (NKs) detect cancer cells despite said mutations - demonstrating increased tumor elimination potential. We developed an NK differentiation system using human pluripotent stem cells (hPSCs). Via this system, genetic modifications targeting cancer treatment challenges can be introduced during pluripotency - enabling unlimited production of modified "off-the-shelf" hPSC-NKs.
Methods: hPSCs were differentiated into hematopoietic progenitor cells (HPCs) and NKs using our novel organoid system. These cells were characterized using flow cytometric and bioinformatic analyses. HPC engraftment potential was assessed using NSG mice. NK cytotoxicity was validated using in vitro and in vitro K562 assays and further corroborated on lymphoma, diffuse intrinsic pontine glioma (DIPG), and GBM cell lines in vitro.
Results: HPCs demonstrated engraftment in peripheral blood samples, and hPSC-NKs showcased morphology and functionality akin to same donor peripheral blood NKs (PB-NKs). The hPSC-NKs also displayed potential advantages regarding checkpoint inhibitor and metabolic gene expression, and demonstrated invitro and invivo cytotoxicity against various cancers.
Conclusions: Our organoid system, designed to replicate invivo cellular organization (including signaling gradients and shear stress conditions), offers a suitable environment for HPC and NK generation. The engraftable nature of HPCs and potent NK cytotoxicity against leukemia, lymphoma, DIPG, and GBM highlight the potential of this innovative system to serve as a valuable tool that will benefit cancer treatment and research - improving patient survival and quality of life.
期刊介绍:
Tumor immunology explores the natural and therapy-induced recognition of cancers, along with the complex interplay between oncogenesis, inflammation, and immunosurveillance. In response to recent advancements, a new journal, OncoImmunology, is being launched to specifically address tumor immunology. The field has seen significant progress with the clinical demonstration and FDA approval of anticancer immunotherapies. There's also growing evidence suggesting that many current chemotherapeutic agents rely on immune effectors for their efficacy.
While oncologists have historically utilized chemotherapeutic and radiotherapeutic regimens successfully, they may have unwittingly leveraged the immune system's ability to recognize tumor-specific antigens and control cancer growth. Consequently, immunological biomarkers are increasingly crucial for cancer prognosis and predicting chemotherapy efficacy. There's strong support for combining conventional anticancer therapies with immunotherapies. OncoImmunology will welcome high-profile submissions spanning fundamental, translational, and clinical aspects of tumor immunology, including solid and hematological cancers, inflammation, and both innate and acquired immune responses.