The importance of animal models in tumor immunity and immunotherapy

Abstract

The clinical success and US FDA approval of two immunotherapies (sipuleucel-T and ipilimumab) have brought tumor immunology to the forefront of cancer research. It has been long recognized that the immune system can infiltrate and survey the tumor microenvironment. The field of tumor immunology has been actively examining this phenomenon since the 1890s when William Coley first treated patients with live pathogenic bacteria and observed occasional regressions leading to long term survival. Recent progress in understanding mechanisms of immune activation and tolerance has led to the development of novel therapies that aim to either overcome inhibitory pathways (i.e. checkpoint blockade such as anti-CTLA-4 and anti-PD-1) or stimulate immune cell activation (i.e. co-stimulation such as anti-GITR and anti-OX40). A major part of the success of immunotherapy has been the development of appropriate mouse models. This review will outline the history and the major findings leading to the accomplishments of modern day immunology with specific attention to the usefulness of animal models.

Figure 1. Research in Tumor Immunology

Timeline of the history of tumor immunology from its inception in the late 1900s with William Coley's experiments to modern day tumor immunology with the FDA approval of 2 immunotherapies for treatment of cancer. Based on current clinical outcomes and laboratory based research using animal models future promising therapies will be combining checkpoint blockade, co-stimulation alone or in combination with conventional approved treatments.

Figure 2. The 3 E's of Cancer Immunoediting

The concept of cancer immunoediting during the course of tumor development consists of three phases Elimination, Equilibrium and Escape. Elimination: during the early phase of tumorigenesis, when tumors are microscopic, the immune system eliminates the highly immunogenic cells leaving the poorly immunogenic ones behind. Equilibrium: as the immunogenic cells are eliminated, tumors enter an equilibrium (or dormant) phase where the immune system prevents tumor growth. Escape: changes in the tumor cells or stroma within the microenvironment can facilitate uncontrolled tumor growth and metastasis. Shown on the right are representative photos of melanoma bearing Grm1 (Glutamate metabotropic receptor) transgenic mice, where tumors regress when mice are treated with immunotherapy (top). Both melanoma cells and melanocytes are eliminated as shown by the absence of tumor and depigmentation of the fur. Histology staining (H and E) of paraffin sections of ear shows no tumor burden with residual melanin. In some instances, tumors are non-responsive to immunotherapy and continue to progress (bottom). Histology staining of these ears show heavy tumor burden.