What question did this study set out to answer?

To create and evaluate novel mouse models that support human NK cell development and function for preclinical studies.

April 5, 2026

Abstract 3392: Development of novel NCG-hIL15 and hIL-2 mouse models for preclinical assessment of human NK cell function

Key Points

To create and evaluate novel mouse models that support human NK cell development and function for preclinical studies.
Developed NCG-hIL2 and NCG-hIL15 mouse models lacking functional T cells, B cells, and NK cells.
Engineered models to express human IL-2 and IL-15 to facilitate NK cell maturation.
Assessed NK cell reconstitution and function following injection of human hematopoietic stem cells.
Conducted preclinical studies with antibody treatments to evaluate therapeutic efficacy.
NCG-hIL2 model showed enhanced reconstitution of human NK cells, demonstrating IL-2's critical role.
NCG-hIL15 supported robust co-engraftment of human NK and T cells, suitable for evaluating combination therapies.
Both models effectively assessed ADCC-mediated antibodies like Trastuzumab and Rituximab.

Abstract

Abstract Natural Killer (NK) cells are critical mediators of antitumor immunity, exerting direct cytotoxicity and secreting immunoregulatory cytokines. They play a particularly important role in antibody-dependent cellular cytotoxicity (ADCC), a key mechanism harnessed by many therapeutic antibodies. To study these mechanisms, humanized mouse models have been employed, however; conventional human immune cell transplanted immunodeficient mouse models poorly support NK cell engraftment, limiting their translational utility. To address this gap, we developed two human cytokine-expressing mouse models on the NCG triple-immunodeficient mouse model that lacks functional T cells, B cells, and NK cells. TheNCG-hIL2 and NCG-hIL15, were engineered to constitutively express human IL-2 and human IL-15, respectively. These models were assessed for their ability to sustain human NK cell development and function after reconstitution with human hematopoietic stem cells (HSCs). The NCG-hIL2 model showed enhanced human NK cell reconstitution, underscoring the essential role of IL-2 in NK cell maturation and survival. In contrast, the NCG-hIL15 model supported robust co-engraftment of human T and NK cells, making it particularly suitable for evaluating combination T and NK cell-directed immunotherapies. Both models were evaluated in preclinical immunotherapy studies. The NCG-hIL2 model proved highly effective for assessing ADCC-mediated antibodies such as Trastuzumab, Margetuximab, Rituximab, and Blinatumomab. Together, the NCG-hIL2 and NCG-hIL15 models provide powerful and complementary platforms for studying human NK cell biology, cytokine-driven immunity, and anticancer immunotherapy. Citation Format: Hongyan Sun, Yinlian Zhang, Yunlong Jiang, Yujing Zhang, Huixin Yang, Xiang Gao. Development of novel NCG-hIL15 and hIL-2 mouse models for preclinical assessment of human NK cell function abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3392.

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