Cancer Immunology, Immunotherapy

, Volume 65, Issue 7, pp 835–845 | Cite as

Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice

  • Anna K. Kozlowska
  • Kawaljit Kaur
  • Paytsar Topchyan
  • Anahid Jewett
Focussed Research Review

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.

Keywords

Osteoclast-expanded NK cells Cancer immunotherapy BLT humanized mice CSCs CITIM 2015 

Abbreviations

CD

Cluster of differentiation

CSC

Cancer stem-like cell

DC

Dendritic cell

hCB

Human cord blood

HLA

Human histocompatibility leukocyte antigen

HSC

Hematopoietic stem cell

HTM

Humanized tumor mice

hu-BLT

Bone marrow, liver, thymus humanized mice

IFN

Interferon

IL

Interleukin

IL2Rγ

Interleukin 2 receptor subunit gamma

K562

Mouse erythroleukemia cell line

MHC

Major histocompatibility complex

NK cell

Natural killer cell

NOD

Non-obese diabetic

NSG

NOD-scid IL2RGnull

OSCSC

Oral squamous cancer stem cell

PD-L1

Programmed death-ligand 1 (also known as B7H1)

PDX

Patient-derived xenografts

PKH

Paul Karl Horan fluorescent dye

Poly(I:C)

Polyinosinic/polycytidylic acid

scid

Severe combined immunodeficiency

TNF

Tumor necrosis factor

Notes

Acknowledgments

Anna K. Kozlowska was supported by the Polish Ministry of Sciences and Higher Education and Mobility Plus award.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Anna K. Kozlowska
    • 1
    • 3
  • Kawaljit Kaur
    • 1
  • Paytsar Topchyan
    • 1
  • Anahid Jewett
    • 1
    • 2
  1. 1.Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive BiotechnologyUCLALos AngelesUSA
  2. 2.The Jonsson Comprehensive Cancer CenterUCLA School of Dentistry and MedicineLos AngelesUSA
  3. 3.Department of Tumor Immunology, Chair of Medical BiotechnologyPoznan University of Medical SciencesPoznanPoland

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