Development of severe combined immunodeficient (SCID) pig models for translational cancer modeling: future insights on how humanized SCID pigs can improve preclinical cancer research

Authors: BOETTCHER, ADELINE - Iowa State University; Loving, Crystal; CUNNICK, JOAN - Iowa State University; TUGGLE, CHRISTOPHER - Iowa State University

Submitted to: Frontiers in Oncology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/9/2018
Publication Date: 11/30/2018
Citation: Boettcher, A., Loving, C.L., Cunnick, J., Tuggle, C. 2018. Development of severe combined immunodeficient (SCID) pig models for translational cancer modeling: future insights on how humanized SCID pigs can improve preclinical cancer research. Frontiers in Oncology. 8:559. https://doi.org/10.3389/fonc.2018.00559.
DOI: https://doi.org/10.3389/fonc.2018.00559

Interpretive Summary: Pigs serve as a biomedical model for performing research that can benefit both animal and humans. The recent derivation of severe combined immunodeficiency (SCID) pigs provides a model for exploration and development of a large animal with a human immune system for studying interaction between the immune system and tumors. Derivation of SCID pigs requires unique environmental conditions for rearing, as animals are susceptible to disease. In addition, there are multiple methods to engraft SCID pigs with human cells, each of which are discussed. Overall, the pig SCID model has significant potential for therapeutic testing.

Technical Abstract: Within the last decade there have been several severe combined immunodeficient (SCID) pig models discovered or genetically engineered. The animals have mutations in ARTEMIS, IL2RG, or RAG1/2 genes, or combinations thereof, providing SCID pigs with NK cells, but deficient in T and B cells, or deficient in NK, T, and B cells for research studies. Biocontainment facilities and positive pressure isolators are developed to limit pathogen exposure and prolong the life of SCID pigs. Raising SCID pigs in such facilities allows for completion of long-term studies such as xenotransplantation of human cells. Ectopically injected human cancer cell lines develop into tumors in SCID pigs, thus providing a human-sized in vivo model for evaluating imaging methods to improve cancer detection and therapeutic research and development. Immunocompromised pigs have the potential to be immunologically humanized by xenotransplantation with human hematopoietic stem cells, peripheral blood leukocytes, or fetal tissue. These cells can be introduced through various routes including injection into fetal liver or the intraperitoneal (IP) space, or into piglets by intravenous, IP, and intraosseous administration. The development and maintenance of transplanted human immune cells would be initially (at least) dependent on immune signaling from swine cells. Compared to mice, swine share higher homology in immune related genes with humans. This suggests that the SCID pig may be able to support improved engraftment and differentiation of a wide range of human immune cells as compared to equivalent mouse models. Humanization of SCID pigs would thus provide a valuable model system for researchers to study interactions between human tumor and human immune cells. Additionally, as the SCID pig model is further developed, it may be possible to develop patient-derived xenograft models for individualized therapy and drug testing. We predict the individualized therapeutic approach would be significantly improved with a humanized SCID pig due to similarities in size, metabolism, and physiology. In all, porcine SCID models have significant potential as an excellent preclinical animal model for therapeutic testing.