T-cells can mediate anti-tumor responses in select patients, but the interaction between T-cells and tumor which can lead to a cytotoxic T-lymphocyte (CTL) response is poorly understood. Our long-range goal is to gain a more fundamental understanding of the mechanisms involved in T-cell recognition of tumor associated antigen (TAA), and the subsequent tumor specific T-cell responses, which can then be translated into more effective approaches to cellular immunotherapy. Growth of tumor despite the existence of TAA specific T-cells suggests that ineffective T-cell recognition/activation may be playing a critical role. Furthermore, the fact that the majority of identified TAA are self proteins raises the question of peripheral tolerance. We propose to use transgenic technology and recently isolated MCA sarcoma reactive TCR genes gain a more fundamental understanding of the possible role of tumor tolerance, the availability/presentation of TAA to naive T-cells, and effects of the local tumor milieu on T-cell response.
Our specific aims are: 1.1-1.3) create and characterize transgenic mice to provide naive tumor specific T-cells, and then create a T-cell chimera utilizing TCR transgenic bone marrow. These will be challenged with tumor to determine whether malignant cells will avoid an effective CTL response despite adequate T-cell precursor frequency.
Specific aims 2. 1-2.3 will utilize transgenic TCR cells to 1) determine whether tumor alone can effectively present TAA to naive T-cells, and 2) define, using adoptive transfer into syngenic mice, the in vivo TAA-dependent clonal expansion and trafficking of tumor specific T-cells. Additionally, we will define the role of CTLA-4 blockade in the generation of an effective CTL response. Finally, specific aim 3.1 will address the effect of tumor micro environment on T-cell response in vivo by transferring activated transgenic T-cells into tumor bearing nude mice and evaluating their subsequent cytokine/activation profile at the local tumor site. The major advantage of this proposal is the creation of naive tumor specific T-cells which enables us to address important questions concerning T-cell activation and response to tumor in a clear and simple manner. The ability to understand these basic mechanisms could potentially lead to more effective forms of therapy for cancer and provide new insight into principles of tumor immunology.
| Nguyen, C L; Bui, J T; Demcheva, M et al. (2001) Sustained release of granulocyte-macrophage colony-stimulating factor from a modular peptide-based cancer vaccine alters vaccine microenvironment and enhances the antigen-specific T-cell response. J Immunother 24:420-9 |
