Mouse versus Human Neutrophils in Cancer: A Major Knowledge Gap

Abstract

Many types of cancer recruit neutrophils that could have protumor or antitumor effects on tumor development. Numerous findings in murine models suggest a predominantly protumoral role for neutrophils in cancer development. However, there are fundamental differences between mouse and human tumors in the evolution of tumors, genetic diversity, immune response, and also in the intrinsic biology of neutrophils that might have a profound impact on tumor development and the function of these cells. A crucial difference is that the majority of mouse tumor models lack the prolonged initial phases of multistage tumor evolution present in humans when antitumoral mechanisms are activated. In this review, we discuss the challenges specific to cross-species extrapolation of neutrophil function during mouse versus human tumor development.

Figure 1. Fundamental differences in genetic heterogeneity, tumor evolution and intrinsic biology of neutrophils might affect neutrophil phenotype and function in mouse versus human tumors

In contrast to humans, laboratory mice used for tumor models are inbred and genetically homogeneous. Moreover, they live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Undoubtedly, this does not reflect relevant aspects of the human immune and inflammatory responses occurred during tumor development. Human tumors evolve slowly and undergo all steps of cancer immunoediting (elimination, equilibrium and escape). At the first steps of the tumor evolution, tumor clones initiation, proliferation and diversification occur along with selective pressure on these tumor clones by anti-tumor immune responses. Some clones may elicit immune responses and be killed, while other clones (brown and black color) may favor the immune tolerance and survive. At these stages anti-tumoral neutrophils (N1) would be expected to develop. Consequent immune selection pressure allows surviving tumor clones to acquire sufficient adaptations that permit immune evasion. Subclones resistant to an immune response will gradually become predominant. Surviving clones form the third phase of immune escape, where pro-tumor mechanisms predominate. At this stage, where anti-tumor response is weak against surviving clones, the accumulation of immunosuppressive N2 neutrophils and/or (Polymorphonuclear Myeloid-Derived Suppressor Cells) PMN-MDSC might be expected. In contrast to human, mouse tumor models use tumor cell lines that are originated from advanced tumors. These tumor cells have already undergone cancer immunoediting and thus are relatively resistant to an immune response. In addition, these tumor cell lines represent a homogenous tumor burden to the immune system that shortly enters the last phase of tumor evolution (escape) after transplantation in mice. This phase is mostly characterized by profound pro-tumoral response with accumulation of immunosuppressive N2 neutrophils and/or PMN-MDSC.