Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
The focus of our work is on the use of dendritic cells (DC) as immunotherapeutic vaccines against melanoma and other malignancies. DC are extremely potent antigen presenting cells (APC) that express MHC class I and class II molecules and an array of costimulatory molecules that are required for the activation of naïve T cells. Thus, DC make ideal candidates as vaccine delivery systems for the generation of immune responses against tumors. Recent studies have demonstrated that many patients make immune responses against their tumors, though they usually ultimately fail to control tumor outgrowth. Extensive investigations have identified many of the proteins that are the targets of these immune responses, and further defined the MHC class I and MHC class II-restricted peptides derived from tumor antigens that are presented to cytotoxic CD8+- and helper CD4+ T cells respectively. DC pulsed with such peptides are the basis of the vaccines that we are currently studying.
Recent studies in our laboratory have indicated that mice immunized with both MHC class I- and class II-restricted peptides derived from an antigen expressed by tumor results in greater control of tumor outgrowth as compared to mice immunized with the MHC class I-restricted peptide alone (Hwang et al, 2007). Further studies have indicated that tumor-specific memory CD4+ T cells enhance the activation, differentiation and, in particular, the infiltration of tumor by secondary CD8+ T cells. As a consequence of this, we are currently studying:
1. Whether the enhanced frequency of tumor-specific CD8+ T cells in the lungs is due to recruitment of central memory CD8+ T cells, or the expansion of effector memory CD8+ T cells. If recruitment is involved, which facets of the memory CD4+ T cells are responsible, and which chemokines and integrins are involved?
2. Is the enhanced activation and differentiation of memory CD8+ T cells due to differential activation of DC by memory CD4+ T cells as compared to naïve CD4+ T cells?
3. Whether other parameters of CD8+ T cell function are enhanced by coordinated reactivation with memory CD4+ T cells.
4. What are the qualitative and quantitative aspects of memory CD4+ T cells that support secondary CD8+ T cell responses to tumor?
5. The parameters of immunization that elicit the most potent CD4+ T cell responses, but not to the detriment of the CD8+ T cell response.
6. Whether cognate or non-cognate CD4+ T cell responses are more supportive of tumor control when tumor is already existent in the host.
As a consequence of our interest in how CD4+ T cells influence CD8+ T cell responses to tumor, our lab has also shown that one of the essential consequences of “licensing” DC via CD40-mediated stimulation is the upregulation of the TNF-superfamily member, CD70 (Bullock, 2005). We have found that the expression of CD70 on DC is not only a biomarker of potently activated DC, but the costimulation rendered by CD70, via its receptor CD27 (which is expressed on most naïve T and B cells, and a subset of NK cells) strongly influences both CD8+ T cell and CD4+ T cell responses to DC vaccines. Current projects in the lab involve:
1. Defining the mechanism by which CD4+ T cells induce the expression of CD70 on DC
2. Determine which other methods of stimulating DC induce CD70 expression on DC.
3. Examining how CD70-mediated costimulation influences the expansion and differentiation of both CD8+ T cell and CD4+ T cell responses.
4. Defining how to utilize CD70-mediated costimulation to enhance immunological control of tumor.
As part of our interest in developing effective immune responses against tumors in humans, our lab is currently studying the phenotype and functionality of CD8+ T cell and CD4+ T cell responses elicited by peptide+adjuvant vaccines administered to melanoma and breast cancer patients at the University of Virginia. By understanding the extent of activation and differentiation of the responding T cells, both in blood and in the tumor, we hope to determine whether any deficiencies exist in the patient’s T cell response, and whether additional interventions may overcome such deficiencies.
Drew J. Roberts, Nathan. A. Franklin, Lara. M. Kingeter, Hideo Yagita, Alison L. Tutt, Martin J. Glennie and Timothy N.J. Bullock; J Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression, of tumor infiltrating CD8+ T cells. Immunother. 2010 Oct;33(8):769-79.PMID: 20842060
Van Deusen, K.E., Rajapakse, R., and Timothy N.J. Bullock. CD70 expression by dendritic cells plays a critical role in the immunogenicity of CD40-independent, CD4+ T cell dependent, licensed CD8+ T cell responses. J Leukoc Biol. 2010 Mar;87(3):477-85. Epub 2009 Dec 1. PMID: 19952354
Hwang, M.L, Lukens, J. and T.N.J. Bullock. Cognate memory CD4+ T cells generated with dendritic cell priming influence the expansion, trafficking and differentiation of recall CD8+ T cells and enhance tumor control. Journal of Immunology, 2007 179(9):5829-38. PMID: 17947656
Bullock T.N.J and H. Yagita. Induction of CD70 on Dendritic Cells through CD40 or TLR Stimulation Contributes to the Development of CD8+ T Cell Responses in the Absence of CD4+ T Cells. Journal of Immunology. 174(2):710-7, 2005. PMID: 15634890
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