Humanized Mouse Models for the Advancement of Innate Lymphoid Cell-Based Cancer Immunotherapies

Abstract

Innate lymphoid cells (ILCs) are a branch of the immune system that consists of diverse circulating and tissue-resident cells, which carry out functions including homeostasis and antitumor immunity. The development and behavior of human natural killer (NK) cells and other ILCs in the context of cancer is still incompletely understood. Since NK cells and Group 1 and 2 ILCs are known to be important for mediating antitumor immune responses, a clearer understanding of these processes is critical for improving cancer treatments and understanding tumor immunology as a whole. Unfortunately, there are some major differences in ILC differentiation and effector function pathways between humans and mice. To this end, mice bearing patient-derived xenografts or human cell line-derived tumors alongside human genes or human immune cells represent an excellent tool for studying these pathways in vivo. Recent advancements in humanized mice enable unparalleled insights into complex tumor-ILC interactions. In this review, we discuss ILC behavior in the context of cancer, the humanized mouse models that are most commonly employed in cancer research and their optimization for studying ILCs, current approaches to manipulating human ILCs for antitumor activity, and the relative utility of various mouse models for the development and assessment of these ILC-related immunotherapies.

Keywords: PDX models; cancer immunotherapy; humanized mice; innate lymphocyte cells; natural killer cell; oncoimmunology.

Figure 1

Different mouse models to study oncoimmunology. In knock-in models, mouse genes are replaced with human counterparts. MISTRG mice have human genes replaced that encode M-CSF, IL-3, GM-CSF, TPO and SIRPα. NOG-IL-15 tg mice have human IL-15 transgene expression. hIL-7xhIL-15 double knock-in mice express human IL-7 and IL-15. SRG-15 mice have the mouse IL-15 gene replaced with the human IL-15 gene. BRGSF mice are Flt3-deficient mice in a BRGS background with exogenous administration of human Flt3L. The O-PDX model consists of orthotopic patient-derived xenografts placed in MISTRG mice. The Hu-PDX mouse model consists of patient-derived xenografts placed in NSG mice with reconstituted human immune systems. Human cancer cell lines can be used in place of PDX in basic cancer immunology and immunotherapy studies. However, PDX models are ideal for the studies of TME biology and certain immunotherapies, e.g. combination immunotherapies.

Figure 2

ILC based immunotherapeutics and mouse models as tools to study them. Immunotherapies that involve ILC antitumor activity can be categorized as antibody-based, cell-based, or other bioengineered immunomodulators. Mouse models such as PD-1 and CTLA-4 knock-in can be used to study checkpoint inhibitors. SCID mice bearing PDX or CDX can be used to study the efficacy of single agent cell therapies such as CAR NK cells or NK92 cells. HIS mice are the most optimal tool to study combination therapies or immunomodulators that may alter the behavior of multiple immune cell types.