title: Adoptive transfer of natural killer cells promotes the anti-tumor efficacy of T cells.
abstract: The density of NK cells in tumors correlates positively with prognosis in many types of cancers. The average number of infiltrating NK cells is, however, quite modest (approximately 30 NK cells/sq.mm), even in tumors deemed to have a "high" density of infiltrating NK cells. It is unclear how such low numbers of tumor-infiltrating NK cells can influence outcome. Here, we used ovalbumin-expressing tumor cell lines and TCR transgenic, OVA-specific cytotoxic T lymphocytes (OT-I-CTLs) to determine whether the simultaneous attack by anti-tumor CTLs and IL-2-activated NK (A-NK) cells synergistically increases the overall tumor cell kill and whether upregulation of tumor MHC class-I by NK cell-derived interferon-gamma (IFNγ) improves tumor-recognition and kill by anti-tumor CTLs. At equal E:T ratios, A-NK cells killed OVA-expressing tumor cells better than OT-I-CTLs. The cytotoxicity against OVA-expressing tumor cells increased by combining OT-I-CTLs and A-NK cells, but the increase was additive rather than synergistic. A-NK cells adenovirally-transduced to produce IL-12 (A-NKIL-12) produced high amounts of IFNγ. The addition of a low number of A-NKIL-12cells to OT-I-CTLs resulted in a synergistic, albeit modest, increase in overall cytotoxicity. Pre-treatment of tumor cells with NK cell-conditioned medium increased tumor MHC expression and sensitivity to CTL-mediated killing. Pre-treatment of CTLs with NK cell-conditioned medium had no effect on CTL cytotoxicity. In vivo, MHC class-I expression by OVA-expressing B16 melanoma lung metastases increased significantly within 24-48h after adoptive transfer of A-NKIL-12cells. OT-I-CTLs and A-NKIL-12cells localized selectively and equally well into OVA-expressing B16 lung metastases and treatment of mice bearing 7-days-old OVA-B16 lung metastases with both A-NKIL-12cells and OT-I-CTLs lead to a significant prolongation of survival. Thus, an important function of tumor-infiltrating NK cells may be to increase tumor cell expression of MHC class-I through secretion of IFNγ, to prepare them for recognition by tumor-specific CTLs.
authors.affiliation: Department of Immunology, University of Pittsburgh Schools of the Health Sciences, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. Electronic address: sgoding@som.umaryland.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Goding
authors.affiliation: Department of Immunology, University of Pittsburgh Schools of the Health Sciences, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Immunology, University of Pittsburgh Schools of the Health Sciences, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Bailey
authors.affiliation: Department of Immunology, University of Pittsburgh Schools of the Health Sciences, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; Department of Surgery, University of Pittsburgh Schools of the Health Sciences, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Department of Immunology, University of Pittsburgh Schools of the Health Sciences, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; UPCI Cell and Tissue Imaging facility at HCC, University of Pittsburgh Cancer Institute, The Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, USA. Electronic address: basse@pitt.edu.
authors.forename: Per H
authors.initials: PH
authors.lastname: Basse
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D005260:Female; D005805:Genes, MHC Class I; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation*; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*
chemical_list: D016207:Cytokines; D010047:Ovalbumin
keywords: Adoptive cell transfer; Cancer immunotherapy; Cell traffic; Cytotoxic T lymphocytes (CTL); Cytotoxicity; Natural killer cells (NK cells)