Myeloid differentiation treatment to diminish the presence of immune-suppressive CD34(+) cells within human head and neck squamous cell carcinomas

Within human head and neck squamous cell carcinomas (HNSCC) that produce granulocyte-macrophage CSF are CD34(+) cells that exhibit natural suppressive (NS) activity. The present study aimed to identify how these NS cells mediate suppression and how to diminish their presence. CD34(+) cells that were immunomagnetically isolated from fresh surgical HNSCC specimens produced a soluble product that blocked normal T cell stimulation through the TCR/CD3 complex, This inhibitory activity could be neutralized with Abs to TGF-beta 1. Since prior studies showed that the CD34(+) NS cells within HNSCC cancers are myelomonocytic progenitor 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 differentiation of the CD34(+) cells predominantly into monocytic cells. The consequence of treating CD34(+) NS cells with the myeloid differentiation 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 activity, 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 differentiation of TGF-beta-secreting CD34(+) NS cells into nonsuppressive monocytic cells that secrete TNF-alpha.