The long-term objective is to develop new approaches for making tumor- specific T cells effective against well-developed, long-established cancers. The emphasis is to study the mechanisms by which two cytokines, TNF and TGF-beta, and one cell type, polymorphonuclear leukocytes (PMN) may affect the growth or immunological destruction of long-term cancers. PMN are important for the establishment of some types of tumors and many well-established tumors are heavily infiltrated with PMN.
The first Aim i s to determine which cytokines attract PMN into the tumors, whether this attraction is direct, and, using KO mice, whether expression of the murine IL8R homologue is required.
The second Aim will determine how the presence or absence of PMN affects tumor cell proliferation and apoptosis. Purified PMN populations will be tested for their capacity to stimulate tumor cell growth in vitro. The effects of depletion of PMN by a granulocyte-specific monoclonal antibody will be tested in vivo.
The third Aim examines the importance of TGF-beta for growth of tumors and on establishment of a """"""""barrier"""""""" that appears to prevent tumor-specific T cells from destroying long-term tumors. TGF-beta is produced by both tumor and host cells. The relative importance of these sources of TGF- beta will be determined by controlling separately the synthesis of TGF- beta by tumors or host cells. Transfecting a dominant negative mutant TGF-beta gene (under the control of a regulatable transactivator) into the tumor cells as well as by introducing this gene into the germline of mice will be used as the approach for selectively abolishing the two principle sources of TGF-beta.
The fourth Aim will determine the mechanisms whereby TNF causes long-term growth arrest of TNF-resistant tumor cells even in T cell-deficient mice. TNF opposes many of the actions of TGF-beta and attracts and also activates PMN. In particular, the role of PMN attracted by TNF and the altered vascular permeability will be analyzed. The fifth Aim is to develop procedures for activating PMN in long-term tumors and for increasing the influx of T cells into such tumors. Granulocyte- specific antibodies will be tested for activation of PMN in vitro and will be used in conjunction with other reagents to increase the effectiveness of specific T cells directed against cancer cells.
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