Metastatic Lewis lung carcinoma (LLC) tumors stimulate myelopoiesis and, consequently, induce bone marrow cells to become immune suppressive to T cell blastogenesis and macrophage activation for tumor necrosis factor α (TNF-α) secretion. The suppressor cells phenotypically resembled granulocytic-monocytic progenitor cells. In order to diminish the presence of these immune suppressor cells, LLC-bearing mice were treated with low doses of γ interferon (IFN-γ) (100 units/mouse) plus TNF-α (10 units/mouse). Treatment of LLC-bearing mice with these low doses of IFN-γ plus TNF-α diminished the suppressive activity of their bone marrow cells, as measured by the effect on normal macrophage activation to secrete TNF-α. In in vivo adoptive transfer studies, bone marrow from placebo-treated LLC-bearers stimulated tumor establishment and metastasis, while the bone marrow of IFN-γ-plus TNF-α-treated tumor-bearers diminished LLC establishment and metastasis. The effect of the low dose treatments with IFN-γ and/or TNF-α on the recurrence of excised s.c. tumors was also assessed. Treatment of mice following tumor excision with either IFN-γ, TNF-α, or the combination of IFN-γ plus TNF-α reduced recurrence. However, in the animals with recurring tumors only the combined IFN-γ plus TNF-α treatment effectively diminished the development of lung metastases. These results demonstrate that low dose IFN-γ plus TNF-α treatment diminishes the presence of suppressor and tumor growth-promoting activities of bone marrow and reduces tumor recurrence and metastasis.
Supported by the Medical Research Services of the Department of Veterans Affairs and by Grants CA-45080 and CA-48080 from the NIH.