Cancer Immunology, Hematology, and Etiology Research
Research funded in the area of cancer immunology and hematology aims to characterize basic biological mechanisms underpinning antitumor immune responses, with an emphasis on immune regulation of the development and spread of tumors and approaches to improve immune targeting and destruction of cancer cells. It also includes research into the molecular bases of hematologic malignancies, including leukemia, lymphoma, multiple myeloma, chronic and acute myeloid leukemia, hematologic cancer stem cells, as well as studies of graft versus host (GVH) disease and the graft versus leukemia (GVL) effect.
Cancer etiology research investigates biological agents and host predisposing states that are possible etiological factors or cofactors in cancer. Biological agents are primarily viruses and bacteria but also include endogenous retroviruses, protozoans, fungi, and other multicellular pathogens involved in the initiation, promotion, or resistance of human cancers. Host predisposing states are those that initiate or promote cancer, such as obesity, diet, comorbid conditions, and aging. Studies in this area also examine the role of developmental and life stages in the susceptibility to etiological factors.
Research in this area is supported and directed by the Cancer Immunology, Hematology, and Etiology Branch (CIHEB).
Antitumor Immunity (Innate and Adaptive)
Achieving a deeper understanding of how the innate and adaptive immune systems regulate antitumor immune responses will inform future cancer immunotherapies. Key research areas include:
- Innate immune effector populations that initiate or carry out antitumor immune responses leading to tumor stasis or eradication such as macrophages, dendritic cells (DCs), neutrophils, mast cells, natural killer (NK) cells, NKT cells, and T cells.
- Regulatory interactions among innate immune cell populations and adaptive immune B and T lymphocytes.
- Regulation (both positive and negative) of adaptive immune T lymphocyte responses to cancer and how these can be optimized to achieve tumor eradication or stasis. Adaptive immune T cell populations include cytolytic T cells (CTL) and helper T cells (Th) - as well as several subsets of each major category - in addition to T regulatory cells (Tregs) that control or inhibit the activities of CTL and Th populations.
B and T Lymphoid Malignancies
Understanding the molecular bases of lymphoid malignancies will elucidate novel molecular targets that these tumors rely on for their growth and survival. A major area of interest encompasses the mechanistic bases of B and T lymphocyte malignancies (leukemia, lymphoma, and myeloma), including:
- Aberrant B cell receptor or T cell receptor signaling
- Increased expression of anti-apoptotic pathways
- Loss of tumor suppressor pathways
- Loss of genome stability (chromosomal translocations and mutation)
- Induction of activation pathways such as the Notch pathway
Hematopoiesis and Myeloid Malignancies (Acute and Chronic)
Acute myeloid leukemia (AML) is a complex disease with considerable phenotypic and genotypic heterogeneity: More than 100 recurring cytogenetic abnormalities have been observed in AML. Most cases of AML are characterized by acquisition of somatic mutations in hematopoietic progenitor cells. These cells have a proliferative and/or survival advantage as well as enhanced self-renewal capacity and impair hematopoietic differentiation. Chronic myeloid leukemia (CML) is a proliferative clonal disorder of hematopoietic stem cells that results primarily in the expansion of mature myeloid cells. However, it also includes expansion of erythroid cells and increased platelets in the peripheral blood. The scope of this research extends from understanding the basic cell biology of hematopoiesis related to leukemogenesis to understanding the molecular lesions that result in leukemogenesis.
Evidence suggests that viruses and other microbes contribute to the etiology of as much as 20 percent of human cancer. The major goal of studies supported in this area is to identify pathways by which pathogens transform human cells and to design strategies to interfere with these processes. Research on biological carcinogenesis seeks to clarify the role of DNA and RNA viruses, bacteria, schistosomes, flukes, and other infectious biological agents in carcinogenesis. Supported research on human or animal virus models include papillomaviruses, gamma herpesviruses, cytomegaloviruses, adenoviruses, hepatitis viruses, polyomaviruses, human T-cell leukemia virus (HTLV), and general retrovirus studies that examine basic virus biology and/or use retroviruses to study basic cellular processes. Hepatocellular carcinoma (HCC) research interests include hepatitis B (HBV) and hepatitis C (HCV) virus studies that examine basic molecular mechanisms, immune evasion, host inflammatory responses, or animal models that recapitulate HCC development.
HIV and AIDS-associated Malignancies
Progress in understanding and treating HIV infection and AIDS has greatly improved patient survival, but this increased survival has been coupled with the development of non-AIDS-defining cancers at higher rates than those observed among the HIV/AIDS-negative population. These cancers include anal, skin, and lung cancers, as well as hepatocellular carcinoma. Continued research is aimed at understanding the complex relationship between HIV infection and antiretroviral therapy in the emergence of non-AIDS-defining cancers.
Bacterial Carcinogenesis and the Role of the Microbiome
Increasing evidence indicates that the human microbiome, particularly GI-resident bacteria, plays an important role in the initiation and progression of cancer. Research funded in this area seeks to determine the role and mechanism of bacterial carcinogens in the colon and in other human cancers and their interactions with other etiologic agents (chemical and viral). The goal of research in this area is to develop tools and preclinical models that will identify and translate discoveries on the molecular mechanisms of biological carcinogens into targets for therapeutic and preventive intervention. Research areas include:
- The etiological role that changes in microflora community structure have on intestinal epithelial cell and mucosal immune homeostasis during carcinogenesis
- Isolation and characterization of infectious agents that may cause or promote tumorigenesis
- Identification of molecular interactions between host cells and pathogens
- Oncogenic host responses to biological agents and their secreted products and metabolites
Host Predisposing States
Host predisposing states include obesity, diet, comorbid conditions, and aging that initiate or promote cancer. A critical aspect of understanding the complex origins of cancer is to identify those factors or conditions that either accelerate or slow cancer progression. Research involving host predisposing states investigates:
- The role of developmental and life stages in the susceptibility to etiological factors
- How diet or dietary components affect carcinogenesis
- The effect of diet on microbial metabolites that are either tumor-protective or tumor-promoting
- Microbial modulation of host genes and factors that affect energy deposition in adipocytes and lean/obese phenotype
- The role of comorbidities such as aging, metabolic syndrome, diabetes, chronic obstructive pulmonary disease (COPD), nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD) as etiological factors in cancer