The long-term objective is to make CD8 + T cell-mediated immunity effective against fully established solid nonhemopoietic tumors, which represent the majority of human cancers. Experimentally, CD8 + T lymphocytes specific for tumor antigens are essential for effective immunity to most cancers. However, once cancers have grown for a week to several weeks, immunizations usually fail to affect tumor growth even though the mice are clearly immunologically responsive to the tumor antigens presented at a different site. Conceptually, the host develops in the tumor a physical and/or immunological """"""""barrier"""""""" which may prevent access of CD8 + T cells to the tumor or inhibit continuing activation/proliferation/survival of these T cells in the tumor and the development of memory. These mechanisms will be examined using TCR transgenic or normal T cells and mice carrying either transplanted tumor fragments in which the antigenic tumor cells are embedded in normal stroma or late established tumors in which the antigen is induced on the tumor cells by genetic recombination.
Aim 1 determines the mechanism causing the impaired immune response to solid non-metastatic tumors, particularly how normal stroma affects antigen release and how direct and indirect presentation the level of antigen expression, and costimulatory inflammation affects the localization, activation and memory formation of responding T cells.
Aim 2 examines how CD8+ T lymphocytes can be made effective against established solid tumors by counteracting or neutralizing the local barrier. It will be determined (i) whether elimination of a Gr-1 + FcR + IgG-TGF-beta-dependent barrier can influence the induction and effector phase of CD8 + T cell immunity in the tumor-bearing host, (ii) how targeting the c-Kit positive myeloid barrier cell with protein-tyrosine kinase inhibitors such as STI571 may be used to permit entry, proliferation and reactivation of CD8 +T cells leading to the destruction of established solid tumors, (iii) how single chain heterominibodies consisting of the V-region of a syngeneic tumor-specific antibody and a costimulatory molecule, T cell survival factor, or lymphoid neogenesis factor, when localized to established solid tumors, may help to overcome the local barrier in solid tumors. Together, studies should lead to a better understanding of how to make CD8 + T cell-mediated immunity effective against fully established solid nonhemopoietic tumors. ? ?
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