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Cancer Immunology, Immunotherapy

, Volume 64, Issue 2, pp 225–235 | Cite as

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

  • Erik Wennerberg
  • Veronika Kremer
  • Richard Childs
  • Andreas LundqvistEmail author
Original Article

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.

Keywords

Adoptive cell therapy Natural killer cells Migration CXCL10 CXCR3 

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

Notes

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.

Conflict of interest

None.

Supplementary material

262_2014_1629_MOESM1_ESM.pdf (324 kb)
Supplementary material 1 (PDF 324 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Erik Wennerberg
    • 1
  • Veronika Kremer
    • 1
  • Richard Childs
    • 2
  • Andreas Lundqvist
    • 1
    Email author
  1. 1.Department of Oncology-Pathology, Cancer Center Karolinska, R8:01Karolinska InstitutetStockholmSweden
  2. 2.Hematology Branch, National Heart, Lung and Blood InstituteNational Institutes of HealthBethesdaUSA

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