title: Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice.
abstract: Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment. In our recent studies, we have observed that oral, pancreatic, and melanoma CSCs were capable of forming large tumors in humanized bone marrow, liver, thymus (hu-BLT) mice with fully reconstituted human immune system. In addition, major human immune subsets including NK cells, T cells, B cells, and monocytes were present in the spleen, bone marrow, peripheral blood, and tumor microenvironment. Similar to our previously published in vitro data, CSCs differentiated with split anergized NK cells prior to implantation in mice formed smaller tumors. Intravenous injection of functionally potent osteoclast-expanded NK cells inhibited tumor growth through differentiation of CSCs in humanized mice. In this review, we present current approaches, advances, and existing limitations in studying interactions of the immune system with the tumor, in particular NK cells with CSCs, using in vivo preclinical hu-BLT mouse model. In addition, we discuss the use of osteoclast-expanded NK cells in targeting cancer stem-like tumors in humanized mice-a strategy that provides a much-needed platform to develop effective cancer immunotherapies.
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.|Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kozlowska
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.
authors.forename: Kawaljit
authors.initials: K
authors.lastname: Kaur
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.
authors.forename: Paytsar
authors.initials: P
authors.lastname: Topchyan
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA. ajewett@ucla.edu.|The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA. ajewett@ucla.edu.
authors.forename: Anahid
authors.initials: A
authors.lastname: Jewett
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000276:immunology*; D010010:Osteoclasts / Q000276:immunology*; D059016:Tumor Microenvironment
keywords: BLT humanized mice; CITIM 2015; CSCs; Cancer immunotherapy; Osteoclast-expanded NK cells