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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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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DOI: https://doi.org/10.1007/s00262-014-1629-5