RANTES SECRETION BY GENE-MODIFIED TUMOR-CELLS RESULTS IN LOSS OF TUMORIGENICITY IN-VIVO - ROLE OF IMMUNE CELL SUBPOPULATIONS

An immunogenic murine fibrosarcoma cell line was genetically modified to express and produce the human RANTES chemokine stably, In in vitro chemotaxis assays purified recombinant human RANTES as well as human R ANTES secreted by the modified murine tumor cells were strongly chemoa ttractant for mouse CD8(+)/Thy-1(+) tumor-infiltrating lymphocytes (TI L), RANTES production did not alter the growth of these cytokine gene- modified tumor cells in vitro, but injection of RANTES-secreting cells resulted in the abolition of the ability of those cells to form solid tumors in vivo. The growth of tumors could be restored by co-administ ration of monoclonal antibodies that inhibit the function of various s ubsets of immune cells, For example, depletion of CD8(+) T cells by an tibody administration resulted in complete restoration of solid tumor formation by RANTES-secreting cells, whereas depletion of the CD4(+) T cell population resulted in a partial restoration of tumor formation, Additionally, administration of an anti-CR3 monoclonal antibody known to inhibit the in vivo migration of macrophages also completely resto red the tumorigenicity of RANTES-secreting fibrosarcoma cells, Thus, t he human RANTES chemokine can abolish tumorigenicity of an immunogenic fibrosarcoma in an in vivo murine model, and this process is mediated by various subpopulations of immune effector cells.