The Department of Cancer Immunology and AIDS investigates fundamental questions in the development and expression of immune responses in cancer and autoimmune disease, as well as the closely related problem of acquired immunodeficiency syndrome (AIDS).
Research goals of the Department include understanding the requirements for effective innate and adaptive host immune responses, and the development of adoptive cellular therapies and vaccines against cancer and AIDS. These efforts are enhanced by collaborative relationships within Dana-Farber/Harvard Cancer Center's Cancer Immunology Program, where Kai Wucherpfennig, MD, PhD, and Glenn Dranoff, MD, adjunct member of CIA, (a member of the Department of Medical Oncology) serve as co-leaders. A cornerstone of the department's mission is training graduate students and postdoctoral fellows. Two NIH-funded training grants, led by Department Chair Harvey Cantor, MD, support postgraduate training in cancer immunology and AIDS research.
Faculty research interests include hematopoiesis and lymphocyte development; innate immunity; antigen-presenting cells; T-cell activation; the Th1 response; regulatory T cells; tumor cell metastasis; cancer vaccines and immunotherapy; human monoclonal antibody-based immunotherapy; viral entry; mechanisms of HIV integration and HIV replication and pathogenesis; and AIDS vaccines.
Recent clinical trials have shown that T cells play a central role in controlling tumor growth. The laboratory of Kai W. Wucherpfennig studies the molecular mechanisms that control T cell receptor recognition of tumor antigens and subsequent signaling events that determine the fate of tumor-infiltrating T cells. Of particular interest are signaling and transcriptional networks that inhibit T cell function in the tumor microenvironment. Insights into these molecular switches may be useful for enhancing the activity of tumor-specific T cells.
A comprehensive understanding of complex biological information systems, including the immune system and nervous system, requires definition of cells that are genetically programmed to suppress signal transmission and inhibit cellular responses. The laboratory of Harvey Cantor has defined a sublineage of regulatory CD8 T cells that are essential to maintain self tolerance. CD8+ Treg are programmed to inhibit the activation and expansion of CD4+ helper T cells; defects in CD8+ Treg result in development of autoimmune disorders, including murine models of lupus, MS and rheumatoid arthritis. Insight into this regulatory T cell subset suggests new therapeutic approaches to autoimmune diseases and cancer.
In the thymus, signaling through the T-cell antigen receptor leading to elimination (negative selection) or differentiation (positive selection) of developing thymocytes generates a self-tolerant T-cell repertoire. Cantor has shown that the serine-threonine kinase MINK connects the T-cell receptor to a signaling pathway that mediates negative, but not positive, selection. Analysis of this pathway indicates that MINK-dependent elimination of self-reactive thymocytes is associated with downstream activation of Jun kinase and enhancement of expression of the pro-apoptotic molecules, Bim and BimEL.
Carl Novina, MD, PhD, studies the role of microRNAs (miRNAs) in T-cell development and T-cell-mediated immune responses. They have shown that two particular miRNAs are highly upregulated during T-cell development in the thymus, but not expressed or expressed at low levels in mature T cells. Current efforts are focused on defining the targets of these miRNAs and their function in normal lymphoid development as well as in leukemias.
Using a pancreatic tumor cell model, Shannon Turley, PhD, studies how the activity of tumor-infiltrating T cells can be increased. Turley is now examining whether cytokine-cytokine receptor complexes can induce tumor regression. Dranoff is developing cancer vaccines with autologous tumor cells engineered to express granulocyte-macrophage colonystimulating factor (GM-CSF). This approach has been translated to clinical trials in multiple cancers and has shown consistent induction of coordinated humoral and cellular immune responses that effectuated substantial tumor destruction. Dranoff also showed that some patients who responded to tumor vaccination or CTLA4 antibody blockade developed high-titer antibodies to the NKG2D ligand MICA. These reactions contributed to tumor destruction by antagonizing immune suppression and augmenting antitumor cytotoxicity.
Studies of mechanisms of HIV-1 integration by Alan Engelman, PhD, unveiled LEDGF, a molecular tether that targets HIV-1 to integrate evenly along transcription units, as a critical gene-targeting factor. His work yielded the first three-dimensional structure of a crucial cell factor bound to a retroviral enzyme.
Dana Gabuzda, MD, studies molecular mechanisms of the interaction of retroviruses with T-cell subsets and the important functional division of labor among subpopulations of monocytes that mediate inflammatory responses. These studies have interesting implications in the twin areas of anticancer and antiviral immunotherapy. Gabuzda also clarified some of the factors underlying HIV cellular tropism.
Joseph Sodroski, MD, discovered a form of innate intracellular immunity against retroviruses mediated by members of the tripartite motif (TRIM) family of proteins. Defining the mechanism by which endogenous proteins, including human TRIM5a, might be enhanced in order to restrict HIV-1 infection in macrophages and microglia has the potential α reverse HIV-1-associated dementia and to have a tremendous impact on HIV-1-associated neurological disorders.
Ruth Ruprecht, MD, PhD, works on AIDS and cancer vaccines and recently demonstrated the ability of overlapping peptides to function as broadly applicable vaccines to defined antigens.
Martin Hemler, PhD, developed an integrin CD151-deficient mouse, which displays impaired tumor-induced angiogenesis and inhibition of breast cancer growth. Von Boehmer showed that APC mice, which develop a high frequency of gastrointestinal cancers, manifest a thymic defect that leads to regulatory T-cell abnormalities. Turley has generated transgenic mice with NFkappaB selectively activated or inhibited to examine the impact of dendritic cell maturation on tumor growth. Wucherpfennig determined the first crystal structure of a T-cell receptor from a human autoimmune disease bound to its self-peptide/MHC target, revealing an unusual topology of peptide/MHC binding that may explain why some autoreactive T cells escape negative selection in the thymus.
Wayne Marasco, MD, PhD, was the first to isolate human neutralizing Abs against SARS-CoVs. Marasco is currently studying the structural and functional basis of broad-spectrum neutralization against avian and human influenza A viruses, with an eye toward developing a universal vaccine against all influenza viruses.
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