Enhanced development of functional human NK cells in NOD-scid-IL2rg(null) mice expressing human IL15.
Enhanced development of functional human NK cells in NOD-scid-IL2rg(null) mice expressing human IL15.
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DOI：
10.1096/fj.202200045r
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发表时间：
2022-09
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人类先天免疫在肿瘤监测和肿瘤微环境免疫调节中起着至关重要的作用。自然杀伤（NK）细胞是在肿瘤微环境中具有相反作用的先天淋巴样细胞，包括介导肿瘤细胞细胞毒性的NK细胞亚群和参与肿瘤免疫抑制环境的具有调节功能的NK细胞亚群。在小鼠癌症模型中，效应NK细胞亚群和调节性NK细胞亚群之间的平衡已经得到了广泛的研究，但研究人类NK细胞在肿瘤发生中的功能的模型却很缺乏。人源化小鼠是人类免疫肿瘤学研究中一种强大的替代小鼠肿瘤模型，并且已被证明是测试针对T细胞的免疫疗法的有效工具。然而，人NK细胞在人源化NOD - scid - IL2rg缺失（NSG）小鼠中的发育和存活受到严重限制。为了促进NK细胞的发育，我们培育了组成性表达人白细胞介素15 （IL15）、NSG‐Tg（Hu‐IL15）的NSG小鼠。在造血干细胞植入NSG - Tg（Hu - IL15）小鼠后，与NSG小鼠相比，在血液和脾脏中检测到明显更高水平的功能性人CD56+ NK细胞。造血干细胞（HSC）植入NSG - Tg（Hu - il - 15）小鼠也支持人CD3+ T细胞、CD20+ B细胞和CD33+骨髓细胞的发育。此外，与移植HSC的NSG - Tg（Hu - IL15）小鼠相比，移植HSC的NSG - Tg（Hu - IL15）小鼠的患者源性异种移植（PDX）黑色素瘤的生长动力学显著延迟，这表明人类NK细胞在限制肿瘤生长方面发挥了关键作用。总之，这些数据表明，HSC植入NSG - Tg（Hu - il - 15）小鼠支持增强功能性人类NK细胞的发育，从而限制了PDX肿瘤的生长。
Human innate immunity plays a critical role in tumor surveillance and in immunoregulation within the tumor microenvironment. Natural killer (NK) cells are innate lymphoid cells that have opposing roles in the tumor microenvironment, including NK cell subsets that mediate tumor cell cytotoxicity and subsets with regulatory function that contribute to the tumor immune suppressive environment. The balance between effector and regulatory NK cell subsets has been studied extensively in murine models of cancer, but there is a paucity of models to study human NK cell function in tumorigenesis. Humanized mice are a powerful alternative to syngeneic mouse tumor models for the study of human immuno‐oncology and have proven effective tools to test immunotherapies targeting T cells. However, human NK cell development and survival in humanized NOD‐scid‐IL2rg null (NSG) mice are severely limited. To enhance NK cell development, we have developed NSG mice that constitutively expresses human Interleukin 15 (IL15), NSG‐Tg(Hu‐IL15). Following hematopoietic stem cell engraftment of NSG‐Tg(Hu‐IL15) mice, significantly higher levels of functional human CD56+ NK cells are detectable in blood and spleen, as compared to NSG mice. Hematopoietic stem cell (HSC)‐engrafted NSG‐Tg(Hu‐IL15) mice also supported the development of human CD3+ T cells, CD20+ B cells, and CD33+ myeloid cells. Moreover, the growth kinetics of a patient‐derived xenograft (PDX) melanoma were significantly delayed in HSC‐engrafted NSG‐Tg(Hu‐IL15) mice as compared to HSC‐engrafted NSG mice demonstrating that human NK cells have a key role in limiting the tumor growth. Together, these data demonstrate that HSC‐engrafted NSG‐Tg(Hu‐IL15) mice support enhanced development of functional human NK cells, which limit the growth of PDX tumors.