title: KLRG1+ NK cells protect T-bet-deficient mice from pulmonary metastatic colorectal carcinoma.
abstract: We studied the developmental and functional mechanisms behind NK cell-mediated antitumor responses against metastatic colorectal carcinoma (CRC) in mice. In particular, we focused on investigating the significance of T-box transcription factors and the immunotherapeutic relevance of IL-15 in the development and function of tumor-reactive NK cells. Pulmonary CRC metastases were experimentally seeded via an adoptive i.v. transfer of luciferase-expressing CT26 CRC cells that form viewable masses via an in vivo imaging device; genetically deficient mice were used to dissect the antitumor effects of developmentally different NK cell subsets. IL-15 precomplexed to IL-15 receptor-α was used in immunotherapy experiments. We found that mice deficient for the T-box transcription factor T-bet lack terminally differentiated antitumor CD27(low)KLRG1(+) NK cells, leading to a terminal course of rapid-onset pulmonary CRC metastases. The importance of this NK cell subset for effective antitumor immunity was shown by adoptively transferring purified CD27(low)KLRG1(+) NK cells into T-bet-deficient mice and, thereby, restoring immunity against lung metastasis formation. Importantly, immunity to metastasis formation could also be restored in T-bet-deficient recipients by treating mice with IL-15 precomplexed to IL-15 receptor-α, which induced the development of eomesodermin(+)KLRG1(+) NK cells from existing NK cell populations. Thus, contingent upon their T-bet-dependent development and activation status, NK cells can control metastatic CRC in mice, which is highly relevant for the development of immunotherapeutic approaches in the clinic.
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Muriel
authors.initials: M
authors.lastname: Malaisé
authors.forename: Jordi
authors.initials: J
authors.lastname: Rovira
authors.forename: Philipp
authors.initials: P
authors.lastname: Renner
authors.forename: Elke
authors.initials: E
authors.lastname: Eggenhofer
authors.forename: Manije
authors.initials: M
authors.lastname: Sabet-Baktach
authors.forename: Margareta
authors.initials: M
authors.lastname: Lantow
authors.forename: Sven A
authors.initials: SA
authors.lastname: Lang
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Koehl
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Farkas
authors.forename: Martin
authors.initials: M
authors.lastname: Loss
authors.forename: Ayman
authors.initials: A
authors.lastname: Agha
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campistol
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Alexander
authors.initials: A
authors.lastname: Kroemer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D018398:Homeodomain Proteins / Q000235:genetics; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics; D019409:Interleukin-15 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D037181:Lectins, C-Type; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism*; D053647:Receptors, Interleukin-15 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: C491198:Eomes protein, mouse; D018398:Homeodomain Proteins; C508025:Il15ra protein, mouse; D019409:Interleukin-15; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D053647:Receptors, Interleukin-15; D011993:Recombinant Fusion Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C510467:perforin 1, mouse; D054353:Perforin; C064658:RAG-1 protein; D007371:Interferon-gamma