Patients with head and neck squamous cell carcinoma (HNSCC) have profound defects in their immune defenses. Using immunofluorescent staining and flow cytometric analysis, we found that most patients with HNSCC have increased levels of CD34+ cells within their peripheral blood. These circulating CD34+ cells contribute to the depressed functional competence of the peripheral blood T-lymphocytes. This was demonstrated by the increased level of proliferative responsiveness to interleukin-2 by the patients' peripheral blood T-cells after depletion of CD34+ cells. These results show the importance of CD34+ cells in contributing to the depression of T-lymphocyte function in patients with HNSCC and suggest that strategies designed to reduce the levels of circulating CD34+ cells may enhance the immune reactivity of the patients' circulating T-lymphocytes against the HNSCC.
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-beta1. 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-beta 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.
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