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CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo

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Abstract

Adoptive infusion of natural killer (NK) cells is being increasingly explored as a therapy in patients with cancer, although clinical responses are thus far limited to patients with hematological malignancies. Inadequate homing of infused NK cells to the tumor site represents a key factor that may explain the poor anti-tumor effect of NK cell therapy against solid tumors. One of the major players in the regulation of lymphocyte chemotaxis is the chemokine receptor chemokine (C-X-C motif) receptor 3 (CXCR3) which is expressed on activated NK cells and induces NK cell migration toward gradients of the chemokine (C-X-C motif) ligand (CXCL9, 10 and 11). Here, we show that ex vivo expansion of human NK cells results in a tenfold increased expression of the CXCR3 receptor compared with resting NK cells (p = 0.04). Consequently, these NK cells displayed an improved migratory capacity toward solid tumors, which was dependent on tumor-derived CXCL10. In xenograft models, adoptively transferred NK cells showed increased migration toward CXCL10-transfected melanoma tumors compared with CXCL10-negative wild-type tumors, resulting in significantly reduced tumor burden and increased survival (median survival 41 vs. 32 days, p = 0.03). Furthermore, administration of interferon-gamma locally in the tumor stimulated the production of CXCL10 in subcutaneous melanoma tumors resulting in increased infiltration of adoptively transferred CXCR3-positive expanded NK cells. Our findings demonstrate the importance of CXCL10-induced chemoattraction in the anti-tumor response of adoptively transferred expanded NK cells against solid melanoma tumors.

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Abbreviations

AML:

Acute myeloid leukemia

BLI:

Bioluminescence imaging

CCR:

C-C chemokine receptor

Cr:

Chromium

CTL:

Cytotoxic T lymphocyte

CXCL:

C-X-C motif ligand

CXCR:

C-X-C motif receptor

DiR:

1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide

DNAM-1:

DNAX accessory molecule-1

DOX:

Doxorubicin

E:T:

Effector-to-target ratio

EBV:

Epstein–Barr virus

FCS:

Fetal calf serum

Gy:

Gray

HLA:

Human leukocyte antigen

I.P:

Intraperitoneally

I.V:

Intravenous

IDO:

Indoleamine 2,3-dioxygenase

IFN:

Interferon

IL:

Interleukin

IP-10:

IFN-gamma-inducible protein 10

I-TAC:

Interferon-inducible T cell alpha chemoattractant

LCL:

Lymphoblastoid cell line

LFA-1:

Leukocyte function-associated antigen 1

LNs:

Lymph nodes

MFI:

Mean fluorescence imaging

MICA/B:

Major histocompatibility complex class I-related chains A and B

MIG:

Monokine induced by gamma interferon

MOI:

Multiplicity of infection

NCRs:

Natural cytotoxicity receptors

NK:

Natural killer

NKG2D:

Natural killer group 2 membrane D

PBMC:

Peripheral blood mononuclear cell

PBS:

Phosphate buffered saline

PCR:

Polymerase chain reaction

PD-L1:

Programmed death-ligand 1

PGE2:

Prostaglandin E2

poly-I:C:

Poly-inositol–cytidine

PVR:

Poliovirus receptor

RCC:

Renal cell carcinoma

S.C:

Subcutaneous

TGF:

Transforming growth factor

TNF:

Tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

ULBPs:

UL16-binding proteins

VLA-4:

Very late antigen-4

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Acknowledgments

We would like to acknowledge the staff at the animal facility at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. Dhifaf Sarhan and Rolf Kiessling at the Department of Oncology-Pathology, Karolinska Institutet for intellectual input. This work was supported by funding from The Swedish Research Council (#522-208-2377), The Swedish Cancer Society (#CAN 2012/474), FP7 Marie Curie re-integration Grant (#246759), The Cancer Society in Stockholm (#121132), the Swedish Society of Medicine (#325751), Karolinska Institutet, Jeanssons Stiftelser, Åke Wibergs Stiftelse, Magnus Bergvalls Stiftelse, Fredrik och Ingrid Thurings Stiftelse, Stiftelsen Clas Groschinskys Minnesfond, and the Division of Intramural Research at the Hematology Branch of the National Heart Blood and Lung Institute.

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Authors and Affiliations

  1. Department of Oncology-Pathology, Cancer Center Karolinska, R8:01, Karolinska Institutet, 171 76, Stockholm, Sweden

    Erik Wennerberg, Veronika Kremer & Andreas Lundqvist

  2. Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Richard Childs

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  1. Erik Wennerberg
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  2. Veronika Kremer
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  3. Richard Childs
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  4. Andreas Lundqvist
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Correspondence to Andreas Lundqvist.

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Parts of the work have been published at the Cold Spring Harbor Asia Conference—Tumor Immunology and Immunotherapy, Oct 28th–Nov 1st 2013, Suzhou, China.

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Wennerberg, E., Kremer, V., Childs, R. et al. CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo. Cancer Immunol Immunother 64, 225–235 (2015). https://doi.org/10.1007/s00262-014-1629-5

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