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Improved Detection of in vivo Human NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity Using a Novel NOG-Fc?R-Deficient Human IL-15 Transgenic Mouse.

ABSTRACT: We generated an NOD/Shi-scid-IL2R? null (NOG) mouse deficient for the Fcer1g and Fcgr2b genes (NOG-Fc?R-/- mice), in which monocytes/macrophages do not express activating (Fc?RI, III, and IV) or inhibitory (Fc?RIIB) Fc? receptors. Antibody-dependent cellular cytotoxicity (ADCC) by innate immune cells was strongly reduced in this strain. Thus, while the growth of xenogeneic human tumors engrafted in conventional NOG mice was suppressed by innate cells upon specific antibody treatment, such growth inhibition was abrogated in NOG-Fc?R-/- mice. Using this novel strain, we further produced NOG-Fc?R-/--mice expressing human IL-15 (NOG-Fc?R-/--hIL-15 Tg). The mice inherited unique features from each strain, i.e., the long-term sustenance of human natural killer (NK) cells, and the elimination of mouse innate cell-mediated ADCC. As a result, segregation of human NK cell-mediated ADCC from mouse cell-mediated ADCC was possible in the NOG-Fc?R-/--hIL-15 Tg mice. Our results suggest that NOG-Fc?R-/--hIL-15 Tg mice are useful for validating the in vivo function of antibody drug candidates.

SUBMITTER: Katano I

PROVIDER: S-EPMC7577188 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Improved Detection of in vivo Human NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity Using a Novel NOG-FcγR-Deficient Human IL-15 Transgenic Mouse.

Katano Ikumi I Ito Ryoji R Kawai Kenji K Takahashi Takeshi T

Frontiers in immunology 20201007

We generated an NOD/Shi-scid-IL2Rγ null (NOG) mouse deficient for the Fcer1g and Fcgr2b genes (NOG-FcγR-/- mice), in which monocytes/macrophages do not express activating (FcγRI, III, and IV) or inhibitory (FcγRIIB) Fcγ receptors. Antibody-dependent cellular cytotoxicity (ADCC) by innate immune cells was strongly reduced in this strain. Thus, while the growth of xenogeneic human tumors engrafted in conventional NOG mice was suppressed by innate c ...[more]

PMID: 33117338

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Project description:NK cells have potent antitumor capacity. They are enriched in the human liver, with a large subset specialized for tissue-residence. The potential for liver-resident versus liver-infiltrating NK cells to populate, and exert antitumor functions in, human liver tumors has not been studied. We examined liver-resident and liver-infiltrating NK cells directly ex vivo from human hepatocellular carcinomas (HCCs) and liver colorectal (CRC) metastases, compared with matched uninvolved liver tissue. We found that NK cells were highly prevalent in both HCC and liver CRC metastases, although at lower frequencies than unaffected liver. Up to 79% of intratumoral NK cells had the CXCR6+CD69+ liver-resident phenotype. Direct ex vivo staining showed that liver-resident NK cells had increased NKG2D expression compared to their non-resident counterparts, but both subsets had NKG2D downregulation within liver tumors compared to uninvolved liver. Proliferation of intratumoral NK cells (identified by Ki67) was selectively impaired in those with the most marked NKG2D downregulation. Human liver tumor NK cells were functionally impaired, with reduced capacity for cytotoxicity and production of cytokines, even when compared to the hypo-functional tissue-resident NK cells in unaffected liver. Coculture of human liver NK cells with the human hepatoma cell line PLC/PRF/5, or with autologous HCC, recapitulated the defects observed in NK cells extracted from tumors, with downmodulation of NKG2D, cytokine production, and target cell cytotoxicity. Transwells and conditioned media confirmed a requirement for cell contact with PLC/PRF/5 to impose NK cell inhibition. IL-15 was able to recover antitumor functionality in NK cells inhibited by in vitro exposure to HCC cell lines or extracted directly from HCC. In summary, our data suggest that the impaired antitumor function of local NK cells reflects a combination of the tolerogenic features inherent to liver-resident NK cells together with additional contact-dependent inhibition imposed by HCC itself. The demonstration that IL-15 can recover hepatic NK cell function following tumor exposure supports its inclusion in immunotherapy strategies.

Dataset Information

Improved Detection of in vivo Human NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity Using a Novel NOG-Fc?R-Deficient Human IL-15 Transgenic Mouse.

Publications

Improved Detection of <i>in vivo</i> Human NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity Using a Novel NOG-FcγR-Deficient Human IL-15 Transgenic Mouse.

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