Area of expertise
Schreiber's work focuses on the concept of immune surveillance in cancer pathogenesis. For over 50 years, scientists have argued about the role of the immune system in preventing the initiation of cancer. The original immune surveillance hypothesis proposed that tumor cells arise naturally and are normally eradicated by the immune system. Tumors would, therefore, only arise if the tumor could develop a mechanism to evade the immune system, or if the immune system were compromised. This hypothesis was directly tested in a landmark paper published by Osias Stutman (1974). [2] In this paper, Stutman tested whether athymic, nude mice which lack an adaptive immune system have an increased incidence of tumors. His finding that the incidence of tumor formation was the same in nude mice, as compared to wild type mice, led to the strong belief, for over 20 years, that the immune system played no role in preventing the initiation or the prevention of tumors. This finding was consistent with the idea that most tumors arise in individuals with normal immune systems. However, a key study published in 2000 by Wilfred Jefferies’ Lab [3] revisited Stutman's experiments using the same nude mouse model and provided the first evidence challenging his conclusions. This was the first study to conclusively demonstrate that the immune system plays a role in controlling tumor formation.
With the explosion of new information about the role of the innate immune system over the last two decades, and with the knowledge that the innate immune system was intact in the nude mice that Stutman had used, Schreiber repeated these experiments using a strain of mice he bred to lack both innate and adaptive immunity. These mice lacked the recombination activating gene (RAG) required for adaptive immune responses and the STAT1 gene that is required for innate responses. Schreiber's lab was the first to generate STAT1 deficient mice and has worked to characterize the important role of this gene in innate immunity. [4]
In 2001, in another landmark paper, Schreiber reported that RAG2 knockout mice, which lack an adaptive immune system (T and B cells), had a dramatically increased rate of tumor formation compared to wild type mice. [5] Collectively, these studies [6] ; invalidated the conclusions of the Stutman study, and revived the idea that the immune system could play a critical role. Subsequent work showed that tumors escape immune recognition by losing their antigenicity in a process Scheiber named cancer immunoediting, and Jefferies termed cancer immune escape [7] .
These studies have been critical in forming the scientific basis of many of the immune mediated strategies currently being tested in patients as anti-tumor regimens. Not only do these studies confirm that the immune system can, in fact, play an important role in destroying tumors, but they support the idea that better understanding of immunological recognition and regulation will lead to breakthroughs in our ability to eradicate tumors using the immune system.
In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization.
A nude mouse is a laboratory mouse from a strain with a genetic mutation that causes a deteriorated or absent thymus, resulting in an inhibited immune system due to a greatly reduced number of T cells. The phenotype of the mouse is a lack of body hair, which gives it the "nude" nickname. The nude mouse is valuable to research because it can receive many different types of tissue and tumor grafts, as it mounts no rejection response. These xenografts are commonly used in research to test new methods of imaging and treating tumors. The genetic basis of the nude mouse mutation is a disruption of the FOXN1 gene.
Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.
Tryptase is the most abundant secretory granule-derived serine proteinase contained in mast cells and has been used as a marker for mast cell activation. Club cells contain tryptase, which is believed to be responsible for cleaving the hemagglutinin surface protein of influenza A virus, thereby activating it and causing the symptoms of flu.
Interferon gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed interferon gamma release assay used to test for tuberculosis. In humans, the IFNG protein is encoded by the IFNG gene.
Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.
Immunogenetics or immungenetics is the branch of Medical Immunology and Medical Genetics that explores the relationship between the immune system and genetics.
Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). It functions as a transcription factor downstream of type I interferons. STAT2 sequence identity between mouse and human is only 68%.
Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.
Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.
Brian K. Kennedy is a scientist, performing research on the science of aging and healthy longevity. Since 2017, he has served as a Distinguished Professor in Biochemistry and Physiology at the Yong Loo Lin School of Medicine in the National University of Singapore, where he is currently the Director of the Healthy Longevity Translational Research Programme and the Asian Centre for Reproductive Longevity and Equality. His efforts have been directed at building world-class longevity research in Singapore.
Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.
Lloyd John Old was one of the founders and standard-bearers of the field of cancer immunology. When Old began his career in 1958, tumor immunology was in its infancy. Today, cancer immunotherapies are emerging as a significant advance in cancer therapy.
Gustav Gaudernack is a scientist working in the development of cancer vaccines and cancer immunotherapy. He has developed various strategies in immunological treatment of cancer. He is involved in several ongoing cellular and immuno-gene therapeutic clinical trials and his research group has put major efforts into the development of various T cell-based immunotherapeutic strategies.
James Patrick Allison is an American immunologist and Nobel laureate who holds the position of professor and chair of immunology and executive director of immunotherapy platform at the MD Anderson Cancer Center in Houston, Texas. Allison is Regental Professor and Founding-Director of James P. Allison Institute at the MD Anderson Cancer Center.
Randy Jirtle is an American biologist noted for his research in epigenetics, the branch of biology that deals with inherited information that does not reside in the nucleotide sequence of DNA. Jirtle retired from Duke University, Durham, NC in 2012. He is presently Professor of Epigenetics in the Department of Biological Sciences at North Carolina State University, Raleigh, NC. Jirtle is noted for his research on genomic imprinting, and for his use of the Agouti mouse model to investigate the effect of environmental agents on the mammalian epigenome and disease susceptibility.
Immunoediting is a dynamic process that consists of immunosurveillance and tumor progression. It describes the relation between the tumor cells and the immune system. It is made up of three phases: elimination, equilibrium, and escape.
The Immunologic Constant of Rejection (ICR), is a notion introduced by biologists to group a shared set of genes expressed in tissue destructive-pathogenic conditions like cancer and infection, along a diverse set of physiological circumstances of tissue damage or organ failure, including autoimmune disease or allograft rejection. The identification of shared mechanisms and phenotypes by distinct immune pathologies, marked as a hallmarks or biomarkers, aids in the identification of novel treatment options, without necessarily assessing patients phenomenologies individually.
Retroelement silencing factor 1 is a protein that in humans is encoded by the RESF1 gene. RESF1 is broadly expressed in the lymph nodes, ovaries, appendix and spleen. RESF1 shows characteristics of being a minor histocompatibility antigen, as well as tumor suppressor capabilities. The high expression in the lymph nodes and spleen indicate function in the immune system.
Carla V. Rothlin is an Argentinian immunologist. She is a professor of immunobiology at Yale University, where she holds the Dorys McConnell Duberg Professorship, and also serves as a professor of pharmacology. Rothlin is the co-leader of the Cancer Immunology Program at Yale Cancer Center and a Howard Hughes Medical Investigator Faculty Scholar.
