SUPPRESSION OF T-CELL PROLIFERATION BY TUMOR-INDUCED GRANULOCYTE-MACROPHAGE PROGENITOR CELLS PRODUCING TRANSFORMING GROWTH-FACTOR-BETA AND NITRIC-OXIDE

Production of high levels of granulocyte-macrophage CSF (CM-CSF) by LL C-LN7 tumors results in myelopoietic stimulation and an increase in ce lls having natural suppressor (NS) activity. Prior studies showed thes e NS cells could be isolated from the bone marrow of tumor-bearing mic e with an Ab (ER-MP12) that recognizes CM-progenitor cells, The presen t study showed these cells to also be in the spleen, lymph node, and t umor, and that treatment of tumor-bearing mice with low doses of IFN-g amma plus TNF-alpha reduced the frequency of ER-MP12(+) cells, Studies focused on characterizing the intratumoral ER-MP12(+) cells and the m echanism by which they suppress T cell proliferation, When isolated an d seeded in soft agar with CSF-containing LLC-LN7 supernatants, the ER -MP12(+) cells grew into colonies, most of which contained both granul ocytic and monocytic cells. Tumor-derived ER-MP12(+) cells and their c ulture supernatants were suppressive to T cell proliferation, Among th e factors produced by ER-MP12(+) cells were TGF-beta, nitric oxide (NO ), IL-10, and prostaglandin E(2) (PGE(2)). However, it was TGF-beta an d NO that mediated the suppression of T cell proliferation by ER-MP12( +) cells, Intratumoral ER-MP12(+) cells could be maintained as suppres sive blastlike cells for at least 4 days in cultures containing CSFs, but adding IFN-gamma plus TNF-alpha to these cultures caused their dif ferentiation mainly into nonsuppressive TNF-alpha-secreting monocytic cells, These results show that intratumoral ER-MP12(+) cells having ho mology to CM-progenitor cells suppress T cell function by producing TG F-beta and NO, IFN-gamma/TNF-alpha treatment stimulates their differen tiation and a shift from production of TGF-beta and NO to production o f TNF-alpha.