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Cancer and Inflammation Program

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Overview

The Cancer and Inflammation Program (CIP) constitutes the major immunologic component of the CCR's inflammation and cancer initiative, which spans the NCI's campuses in Frederick and Bethesda and seeks to partner NCI's expertise in inflammation and immunology with its cutting-edge cancer etiology and carcinogenesis program. The CIP is formed by the Laboratory of Experimental Immunology (LEI) together with the Laboratory of Molecular Immunoregulation (LMI). The program also supervises three core laboratories: the CCR Flow Cytometry Facility at Frederick, the CIP Genetics Facility, and the CIP Synthetic Biological Facility.

Recent studies are shedding a new light on how innate resistance, as an integral part of inflammation, and adaptive immunity participate in oncogenesis and tumor surveillance. For a long time, innate resistance was considered a primitive nonspecific form of resistance to infections that was eclipsed by the potent and specific acquired immunity of higher organisms. More recently, it has been recognized that innate resistance is not only the first line of defense against infections but also sets the stage and is necessary for the development of adaptive immunity. Advances in cancer biology now reveal that what used to be considered the defensive mechanisms of innate resistance and inflammation are indeed manifestations of tissue homeostasis and control of cellular proliferation that have many pleiotropic effects on carcinogenesis and tumor progression and dissemination. The interaction of the inflammatory mediators and effector cells with carcinogenesis and tumor progression is complicated and results in effects that either favor or impede tumor progression.

The investigators at the LEI conduct studies on basic mechanisms of innate resistance, inflammation, and adaptive immunity, their pharmacological modulation by biological response modifiers as well as the application of these studies to the understanding of the control of the carcinogenesis process and to cancer therapy/prevention. Basic science approaches utilize experimental animal studies as well as cellular, biochemical, and molecular techniques to study the regulation of cell-mediated immune effector mechanisms, cytokine gene expression and function, biochemistry of receptor-mediated signaling in leukocytes, and the biology of growth factors as they relate to cancer and other diseases. Based on cellular and molecular evaluation of biologicals, this information is then translated into immune modulation and immunotherapy protocols in experimental animals, and hypotheses suitable for testing in cancer patients are formulated.

The LEI is composed of 12 sections:

- The Molecular Immunology Section (Dr. Steve Anderson) investigates the mechanisms controlling selective gene activation in the immune system.

- The HLA Immunogenetics Section (Dr. Mary Carrington) investigates the host genetic effects on human disease. The primary candidates include the HLA class I and II genes located within the human Major Histocompatibility Complex (MHC), because of their central role in the immune response.

- The Human Genetics Section (Dr. Michael Dean) is to develop methods for analyzing complex diseases and to apply them to human genetic conditions, such as cancer, HIV infection, and other diseases.

- The Protein Interactions Section (Dr. Dimiter Dimitrov) focuses on development of human monoclonal antibodies including isolated engineered antibody domains for prevention and treatment of cancer and other diseases.

- The Inflammation and Tumorigenesis Section (Dr. Yingling Hu) studies the mechanism of skin tumorigenesis, the effect of inflammatory microenvironments on skin tumorigenesis in the absence of IKKalpha, and the role of IKKalpha in the development of lymph cells and organs.

- The Immune Modulation Section (Dr. Dennis Klinman) studies immunostimulatory and immunosuppressive agents, their ability to alter the immune milieu, and their impact on the development of inflammatory and oncogenic processes.

- The Leukocyte Signaling Section (Dr. Daniel McVicar) dissects the signaling cascades of leukocyte regulatory receptors including the TREM, KIR, and Ly49s toward an understanding of the mechanisms underlying the innate immune system role in the development of, and subsequent response to, cancer.

- The Structural Bioinformatics Section (Dr. Ruth Nussinov) is focusing on the key role and principles of allostery under normal conditions, in disease and in allosteric drug discovery.

- The Molecular Immunotherapy Section (Dr. Thomas Sayers) studies the molecular amplification of apoptotic signaling in tumor cells by TNF family members, and assesses the therapeutic benefit of this molecular targeting approach alone or in combination with immunotherapy in various mouse tumor models

- The Cancer Immunobiology Section (Dr. Giorgio Trinchieri) studies the role of dendritic cells, other innate or adaptive effector cell types, and pro-inflammatory or immunoregulatory cytokines on carcinogenesis and cancer therapy.

- The Experimental Therapeutics Section (Dr. Robert Wiltrout) studies the cellular and molecular mechanisms by which cytokines regulate inflammation and host anti-tumor immune responses in vivo, particularly as they relate to the complex cellular interactions between the tumor and organ microenvironments. The ETS performs preclinical trials using combinations of immunomodulatory cytokines in rodent tumor models and translates results to the applicability to clinical trials in humans.

- The Cellular and Molecular Immunology Section (Dr. Howard Young) studies the molecular mechanism(s) of cytokine-induced gene expression in leukocytes. A primary focus of research is on IFN-gamma, an important marker of inflammation and the host immune response.

The investigators at the LMI perform fundamental research studies of the role of cytokines and chemokines in inflammation, immunity, angiogenesis, and cancer. LMI scientists engage in the discovery, identification and characterization of new cytokines, study the action of cytokines on target cells (studies of receptors, second and third messengers), determine effects on cell differentiation and cell death pathways and study cytokine regulation of pathophysiological processes.

The LMI is composed of 4 sections:

- The, head of the Immunological Cytokine Research Section (Dr. Scott Durum) is investigating the role of cytokines such as IL7 in the development of T lymphocyte and natural killer cell lineages and their role in promoting cell survival, terminal differentiation and apoptotic cell death.

-The Tumor Immunity and Tolerance Section (Dr. Andy Hurwitz) is pursuing studies of the close relationship of autoimmunity and tumor immunity in animal models being vaccinated to treat melanoma and immunosuppressed to treat autoimmune states (e.g., EAE). The investigators in the Section are also evaluating the effect of inflammation and immunity on prostate tumors in mice.

- The Chemoattractant Receptor and Signal Section (Dr. Ji Ming Wang) is engaged in studies on the role of chemoattractant receptors such as FPR and FPRL-1 in the pathogenesis of neurodegenerative diseases and tumor progression of glioblastomas.

- The Cellular Immunology Section (Dr. Joost Oppenheim) is studying the structure/function relationships of the family of chemoattractant cytokines. These investigators are investigating the role of chemokines in inflammation, immunity, and chemokine mimics such as defensins and autoantigens. They are also investigating the regulation of angiogenesis by chemokines and identifying chemokine inhibitors and immuno-regulatory molecules present in natural products. The investigators in this Section are also investigating the pathophysiological consequences of receptor cross-talk in regulating the functions of receptors for pain and chemokines.

Adjunct Investigators
Dr. Li Yang (Head, Tumor Microenvironment Section, Laboratory of Cancer Biology and Genetics, CCR) is investigating the mechanisms of tumor-host interaction underlying tumor initiation, invasion and metastasis, with the emphasis on the contribution of TGF-beta signaling and COX-2 pathway.

Core Facilities

CCR Flow Cytometry Facility at Frederick - Kathleen Noer, Head

CIP Genetic Core Facility - Dr. Colm O'Huigin, Head

CIP Synthetic Biologics Core - Dr. Nadya Tarasova, Head

This page was last updated on 7/2/2014.