The long-term objective of this study is to supplant the bone marrow- derived suppressor cells in tumor bearers with tumoricidal macrophages so as to achieve immunological tumor rejection. This will be accomplished in mice bearing cloned metastatic Lewis lung carcinoma (LLC-C3) tumors with myeloid differentiation therapy to drive suppressor cell maturation into nonsuppressive tumoricidal monocytes. The differentiation therapy will be comprised of low doses of recombinant murine interferon-gamma (IFN-gamma) plus recombinant human tumor necrosis factor-alpha (TNF). The rationale for this treatment is based on studies showing that LLC-C3 tumors stimulate myelopoiesis leading to the appearance of immature monocytic suppressor cells and that IFN-gamma and TNF synergize to induce maturation of immature myeloid cells into mature tumoricidal monocytes. Initially, the bone marrow-derived suppressor cells in the bone marrow, spleen, blood and tumor mass of LLC-C3-bearing mice will be driven to mature into nonsuppressive tumoricidal monocytes using myeloid differentiation therapy. Successful elimination of suppressor cells by myeloid differentiation therapy will be evidenced both in vitro by deletion of cells which phenotypically and functionally resemble suppressor cells and in vivo by elimination of tumor growth-promoting activity from cells adoptively transferred together with LLC-C3 tumor cells into recipient mice. Finally, the myeloid differentiation therapy will be used to reduce LLC-C3 tumor progression and to prolong host survival. As a result of this study, a novel therapeutic approach will be identified for replacing suppressor cells in tumor bearers with activated macrophages having the ability to kill tumor. This therapeutic approach to drive differentiation of bone marrow-derived suppressor cells into mature cytolytic monocytes will augment anti-tumor defenses and inhibit tumor progression.
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