title: CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo.
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.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, R8:01, Karolinska Institutet, 171 76, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Wennerberg
authors.forename: Veronika
authors.initials: V
authors.lastname: Kremer
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundqvist
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D054357:Chemokine CXCL10 / Q000276:immunology* / Q000378:metabolism; D019743:Chemokines, CXC / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D054367:Receptors, CXCR3 / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D054367:Receptors, CXCR3; D004317:Doxorubicin; D007371:Interferon-gamma