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.
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. [3]
In 2001, in a 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. [4] This study 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 he named cancer immunoediting. [1]
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.
Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.
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, 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.
Members of the signal transducer and activator of transcription (STAT) protein family are intracellular transcription factors that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. They are primarily activated by membrane receptor-associated Janus kinases (JAK). Dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis which enhances the survival of tumors and immunosuppression. Gene knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
Interferon gamma (IFN-γ) 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 IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ 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.
The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cytoband over approximately 400 kb including coding genes for IFNα, IFNω (IFNW1), IFNɛ (IFNE), IFNк (IFNK) and IFNβ (IFNB1), plus 11 IFN pseudogenes.
Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.
Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.
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). STAT2 sequence identity between mouse and human is only 68%.
Cancer immunology is an interdisciplinary branch of biology 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.
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.
The pluripotency of biological compounds describes the ability of certain substances to produce several distinct biological responses. Pluripotent is also described as something that has no fixed developmental potential, as in being able to differentiate into different cell types in the case of pluripotent stem cells.
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.
Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.
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.
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disease. It is a primary immunodeficiency featured by molecular defects in IL12/IFNγ dependent signalling pathway, leading to increased susceptibility to local or disseminated infections by environmental mycobacteria, Mycobacterium bovis Bacille Calmette-Guerin strain, nontyphoidal and typhoidal Salmonella serotypes.
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.
