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

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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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

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Acknowledgments

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

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Authors and Affiliations

  1. Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA

    Anna K. Kozlowska, Kawaljit Kaur, Paytsar Topchyan & Anahid Jewett

  2. The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA

    Anahid Jewett

  3. Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland

    Anna K. Kozlowska

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  1. Anna K. Kozlowska
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  2. Kawaljit Kaur
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Correspondence to Anahid Jewett.

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This paper is a Focussed Research Review based on a presentation given at the Fourth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2015), held in Ljubljana, Slovenia, 27th–30th April 2015. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Kozlowska, A.K., Kaur, K., Topchyan, P. et al. Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice. Cancer Immunol Immunother 65, 835–845 (2016). https://doi.org/10.1007/s00262-016-1822-9

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