Modeling Tumor Immunology and Immunotherapy in Mice

Abstract

Figure 1. Main Applications of Mouse Models for Tumor Immunology and Immunotherapy. Immunodeficient mice xenografted with human cancer cell lines have been at the foundation of in vivo cancer research for several decades, providing ground for the regulatory approval of multiple chemotherapeutics and targeted anticancer agents, but are intrinsically unsuitable for studying tumor immunology and immunotherapy. Similarly, patient-derived xenografts (PDXs) established in immunodeficient mice are not subjected to immunosurveillance by the host, although (depending on the protocol employed for PDX generation) some components of the patient's immune system may also be transferred to the mouse and be active, at least for some time. Considerable efforts are being devoted to the generation of humanized mice to circumvent these limitations. The establishment of PDXs in immunodeficient mice that are also engrafted with matched patient-derived peripheral blood mononuclear cells (PBMCs) is also being investigated as a means to screen for the efficacy of (immuno)therapeutic agents in support of clinical decision making. Mouse cancer cell lines grafted subcutaneously or orthotopically in immunocompetent syngeneic hosts have been instrumental for the development of a variety of immunotherapeutics, as well as for the discovery that conventional anticancer regimens, including some forms of chemotherapy and radiation therapy, can trigger tumor-targeting immune responses. Carcinogen-driven tumors established in immunocompetent versus immunodeficient animals were critical in the early days of modern tumor immunology, as they enabled the discovery of natural anticancer immunosurveillance. Moreover, they allow for investigating the immunological versus non-immunological efficacy of anticancer (immuno)therapeutics in the context of natural immunoediting, clinically relevant immunobiological heterogeneity, and high mutation load. Transgene-driven tumors have generated in-depth insights into the crosstalk between oncogenic drivers and the tumor microenvironment, in both its immunological and non-immunological components. Each of these models is associated with specific advantages and disadvantages (see Key Facts). Figure 2. Key Features of Mouse Models for Tumor Immunology and Immunotherapy. Key parameters that should be taken into careful consideration when choosing the most appropriate mouse model for the study of tumor immunology and immunotherapy include not only the immunological competence of the host (which is influenced by strain, sex, and age) and its immunological compatibility with malignant cells (which is dictated by strain), but also the mutational load of the latter, their immunological history (previous immunoediting), proliferative potential, propensity for neovascularization and metastatic dissemination, as well as their ability to generate an immunostimulatory versus immunosuppressive microenvironment. Inoculation site is also an important parameter to keep under consideration (not shown). The precise objective of each study dictates which specific combination of such features should be preferred.

Keywords: Carcinogen-driven tumors; humanized mice; immunological memory; patient-derived xenografts; transgene-driven tumors; xenografts.