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-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.
Young
M R
MR
Research Service, Hines Veterans Affairs Hospital, IL 60141, USA.
Wright
M A
MA
Pandit
R
R
D018952:Antigens, CD34 / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000494:pharmacology*; D007962:Leukocytes / Q000276:immunology* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018952:Antigens, CD34; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma