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1017 A tumor model in the humanized immuno-reconstituted hIL15 transgenic mice revealed the impact of other immune components on the development and function of NK cells against malignancies
  1. Li Yang,
  2. Chunlei Dai,
  3. Hongmei Xu,
  4. Hui Qi,
  5. Xuzhen Tang,
  6. Qingyang Gu and
  7. Qunsheng Ji
  1. WuXi AppTec, Shanghai, China


Background The roles of natural killer (NK) cells, in the process of immunosurveillance and elimination against malignancies, have been increasingly interesting in the space of immuno-oncology. The utilization of humanized mice, reconstituted with human immune cells, improves the translational relevance of animal models in this field. However, it remains a challenge for the effective reconstitution of human NK cells in mice, due to the lack of human cytokines which are essential for the development of NK. Typically, IL-15 humanization could promote the differentiation, function, and survival of NK in such models. Nevertheless, few studies have been conducted to evaluate the impact of IL-15 humanization on a wider range of human immune cell lineages in a comprehensively immuno-reconstituted system.

Methods To understand this, we conducted a study comparing the reconstitution of human NK alone or in a mixture with the autologous PBMC, in the hIL-15-expressing NOD-scid IL2Rg null mice. NCI-H929 human myeloma was established in each mouse, for the evaluation of anti-tumor efficacy by the immunotherapies targeting NK-mediated cell killing. The frequencies of human immune cells in both the circulation and the tumor microenvironment were evaluated by flow cytometry.

Results As a result, the mixed system of NK/PBMC reconstitution achieved a better reconstitution rate of NK cells compared to the NK-alone system. But the anti-tumor efficacy by anti-CD47 or anti-CD38, in contrast to the higher NK frequency, appeared to be poorer in the NK/PBMC-mixed system. To investigate the underlying mechanism, we analyzed the phenotyping of each immune sub-lineages and found an extremely high frequency of hCD4+ cell in the NK/PBMC mixed system.

Conclusions One possible reason for the inversion between NK frequency and drug efficacy might be the enrichment of hCD4+ sub-lineages including Treg, which were promoted by IL-15, suppressed the NK effector function, and compromised the relevant immuno-therapy. Further studies could be suggested including a deeper look into the phenotyping of TILs, combining with a Treg targeting therapy like anti-CTLA4, and studying the mechanism of interaction between Treg and NK. In summary, given the complexity with the function of various immune components co-existing in the system, an appropriate method of immune reconstitution is critical for the evaluation of cancer immuno-therapies utilizing humanized models.

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