MYELOID DIFFERENTIATION TREATMENT TO DIMINISH THE PRESENCE OF IMMUNE-SUPPRESSIVE CD34(-CELL CARCINOMAS() CELLS WITHIN HUMAN HEAD AND NECK SQUAMOUS)

Within human head and neck squamous cell carcinomas (HNSCC) that produ ce granulocyte-macrophage CSF are CD34(+) cells that exhibit natural s uppressive (NS) activity. The present study aimed to identify how thes e NS cells mediate suppression and how to diminish their presence. CD3 4(+) cells that were immunomagnetically isolated from fresh surgical H NSCC specimens produced a soluble product that blocked normal T cell s timulation through the TCR/CD3 complex, This inhibitory activity could be neutralized with Abs to TGF-beta 1. Since prior studies showed tha t the CD34(+) NS cells within HNSCC cancers are myelomonocytic progeni tor cells, the feasibility of using cytokines that can induce myeloid cell differentiation to diminish the presence of CD34(+) NS cells was tested, Adding low doses of 100 U/ml IFN-gamma plus 10 U/ml TNF-alpha to bulk cultures of dissociated HNSCC cancers diminished the frequency of CD34(+) cells, Studies with CD34(+) cells that were isolated from the HNSCC cancers showed that this cytokine treatment induced differen tiation of the CD34(+) cells predominantly into monocytic cells. The c onsequence of treating CD34(+) NS cells with the myeloid differentiati on treatment was the loss of suppressive activity, a decline in TGF-P production, and the production of TNF-alpha by the resulting monocytic cells, In HNSCC bulk cultures containing high levels of CD34(+) NS ac tivity, IFN-gamma/TNF-alpha not only reduced CD34(+) cell levels, but also increased the capacity of the intratumoral T cells to express the p55 IL-2R. These studies show that IFN-gamma/TNF-alpha can induce dif ferentiation of TGF-beta-secreting CD34(+) NS cells into nonsuppressiv e monocytic cells that secrete TNF-alpha.