In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6026-6026
Abstract:
Humanized mice with human hematopoietic and immune systems have been frequently used for examining in vivo anti-cancer effects of various drugs, including immune checkpoint inhibitors (ICIs) like anti-PD-1 or anti-CTLA-4 antibodies, yet the reliability of the mouse models to be improved. We have recently developed NOD-scid, IL-2Rγ KO (NOG) mice deficient for the mouse FcεRI and FcγIIb genes, thus lacking the expression of functional mouse FcγRs, (NOG-FcγR-/-) and the activity of endogenous antibody-dependent cellular cytotoxicity (ADCC). Reconstitution experiments with human hematopoietic stem cells (HSC) showed that NOG-FcγR-/- mice had higher engraftment capacity for human leucocytes than NOG mice, namely the numbers of HSC-derived human CD19+ B cells and CD33+ myeloid cells, but not CD3+ T cells, were higher in the various tissues in NOG-FcγR-/- mice than those in NOG mice. In tumor-bearing experiments using those reconstituted mice, it was of interest that humanized NOG-FcγR-/- mice (huNOG-FcγR-/-) could invoke strong tumor growth suppression or rejection in response to anti-PD-1 antibody (Nivolumab) treatment in several cancer cell lines, which was absent in conventional huNOG mice. Accordingly, Nivolumab treatment in huNOG-FcγR-/- mice induced a significant increase of human T cells in number in the spleen and infiltration of human T cells with Granzyme B and Perforin-expression into tumor. Furthermore, the composition of activated T cells was different between huNOG-FcγR-/- and huNOG mice. HuNOG-FcγR-/- mice had elevated numbers of activated T cells, both T central memory cells (TCM) and T effector memory cells (TEM), whereas huNOG mice showed an opposite trend, reduced TCM and TEM and increase of naïve T cells. Our results suggest that the novel NOG-FcγR-/- mice become a good model for elucidating the cellular and molecular mechanisms of human tumor rejection by human T cells, and that they will provide a superior in vivo platform for evaluation of anti-cancer drugs, especially, in combination with ICIs like Nivolumab. Citation Format: Ikumi Katano, Asami Hanazawa, Iyo Otsuka, Takuya Yamaguchi, Misa Mochiduki, Kenji Kawai, Ryoji Ito, Motohito Goto, Takahiro Kagawa, Takeshi Takahashi. A novel humanized mouse model based on NOG-FcgR-/-mice recapitulates anti-tumor immune reactions by human immune systems in response to anti-PD-1 antibody (Nivolumab) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6026.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-6026
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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