KLRG1+ NK cells protect T-bet-deficient mice from pulmonary metastatic colorectal carcinoma

• Published in: The Journal of immunology (1950) 2014-02, Vol.192 (4), p.1954-1961
• Main Authors: Malaisé, Muriel, Rovira, Jordi, Renner, Philipp, Eggenhofer, Elke, Sabet-Baktach, Manije, Lantow, Margareta, Lang, Sven A, Koehl, Gudrun E, Farkas, Stefan A, Loss, Martin, Agha, Ayman, Campistol, Josep M, Schlitt, Hans J, Geissler, Edward K, Kroemer, Alexander
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Cell Differentiation - immunology; Cells, Cultured; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Homeodomain Proteins - genetics; Immunotherapy; Interferon-gamma - genetics; Interleukin-15 - metabolism; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Mice; Mice, Inbred BALB C; Mice, Knockout; Perforin; Pore Forming Cytotoxic Proteins - genetics; Receptors, Immunologic - metabolism; Receptors, Interleukin-15 - metabolism; Recombinant Fusion Proteins - therapeutic use; T-Box Domain Proteins - deficiency; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1300876

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.