Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research

Abstract

The immune system plays dual roles in response to cancer. The host immune system protects against tumor formation via immunosurveillance; however, recognition of the tumor by immune cells also induces sculpting mechanisms leading to a Darwinian selection of tumor cell variants with reduced immunogenicity. Cancer immunoediting is the concept used to describe the complex interplay between tumor cells and the immune system. This concept, commonly referred to as the three E’s, is encompassed by 3 distinct phases of elimination, equilibrium, and escape. Despite impressive results in the clinic, cancer immunotherapy still has room for improvement as many patients remain unresponsive to therapy. Moreover, many of the preclinical results obtained in the widely used mouse models of cancer are lost in translation to human patients. To improve the success rate of immuno-oncology research and preclinical testing of immune-based anticancer therapies, using alternative animal models more closely related to humans is a promising approach. Here, we describe 2 of the major alternative model systems: canine (spontaneous) and porcine (experimental) cancer models. Although dogs display a high rate of spontaneous tumor formation, an increased number of genetically modified porcine models exist. We suggest that the optimal immuno-oncology model may depend on the stage of cancer immunoediting in question. In particular, the spontaneous canine tumor models provide a unique platform for evaluating therapies aimed at the escape phase of cancer, while genetically engineered swine allow for elucidation of tumor-immune cell interactions especially during the phases of elimination and equilibrium.

Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

“…To improve the success rate of immuno-oncology research and preclinical testing of immune-based anticancer therapies, preclinical models are being further refined to improve the tumoral immunogenicity by including humanised mouse models, genetically re-engineered mouse models, organoids and mammospheres derived from human tumor stem cell precursors, and ex vivo technology, as well as using alternative animal models more closely related to humans [180]. Dogs have been proposed as a powerful preclinical model of cancer immune therapeutics, serving as a bridge between laboratory animal models and humans [181,182]. By presenting intact immune systems that closely resemble the human immune system and by having analogous, spontaneous oncogenesis that elicits similar immune responses, pets can model key clinical outcomes such as efficacy, dose response and toxicity [183,184].…”

Perspective: Humanized Pig Models of Bladder Cancer

“…The porcine immune system is similar to humans, and they are composed of the same immune cell populations (Meurens et al, 2012). In this sense, pigs are proposed as excellent immune-oncology platforms (Overgaard et al, 2018). Besides, both humans and swine require similar mutations to transform normal cells into tumor cells (Adam et al, 2007).…”

Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA‐Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

“…Hence, the use of appropriate large animal models of cancer that more closely recapitulate the processes involved in tumor initiation, progression, and pathogenesis in humans, would be a valuable approach. [ 27 ] Spontaneous canine tumors of liver are suitable models for human cancer studies, resulting in their use in biodistribution, pharmacokinetic, and efficacy studies on novel anticancer drugs. Liver tumors constitute 12.5% of all tumors in dogs, and are usually malignant.…”