STIMULATION OF IMMUNE SUPPRESSIVE CD34-MARROW BY LEWIS LUNG-CARCINOMATUMORS( CELLS FROM NORMAL BONE)

Progressive growth of metastatic Lewis lung carcinoma (LLC-LN7) tumors is associated with increased levels of bone-marrow-derived CD34+ cell s having natural suppressor (NS) activity toward T cells. The present studies determined whether tumor-derived products are responsible for this induction of NS activity. Culturing normal bone marrow cells with LLC-LN7-conditioned medium (LLC-CM) or with recombinant granulocyte/m acrophage-colony-stimulating factor (GM-CSF) resulted in the appearanc e of NS activity. The development of NS activity coincided with a prom inent increase in the levels of CD34+ cells. That the CD34+ cells were responsible for the NS activity of the bone marrow cultures containin g LLC-CM was shown by the loss of NS activity when CD34+ cells were de pleted. The stimulation of CD34+ NS cells by LLC-CM was attributed to tumor production of GM-CSF, since neutralization of GM-CSF within the LLC-CM reduced its capacity to increase CD34+ cell levels. Studies als o showed that the induction of CD34+ NS cells by LLC-CM and GM-CSF cou ld be overcome by including in the cultures an inducer of myeloid diff erentiation, 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3]. These r esults demonstrate that the mechanism by which the LLC-LN7 tumors stim ulate increased levels of CD34+ NS cells from normal bone marrow is by their production of GM-CSF and that this can be blocked with the myel oid differentiation inducer 1,25(OH)2D3.