Featured Research Project
Tumor-associated Endothelial Cell (TAEC) and Immune Inhibitory CD34+ Progenitor Cells Subvert Immune Defenses: Head and neck squamous cell carcinoma (HNSCC) is a major cancer problem in South Carolina. In studying this disease, Dr. M. Rita I. Young has noted that these tumors avoid the immune response. However, the complete mechanism for this is only now being defined. Although TAECs have been studied extensively in terms of angiogenesis, their potential contribution to tumor-associated immunosuppression has received scant attention. Dr. Young was among the first to definitively demonstrate that TAECs are immunosuppressive in vitro and in vivo. They play a critical role in immune evasion, and these effects are associated at least in part with the production of pro-inflammatory signals.
Dr. Young showed that isolated TAECs produce large quantities of pro-inflammatory molecules, including PGE2 and interleukin 6 (IL-6), and are potent suppressors of TCR-triggered T-cell proliferation. In culture, TAECs can force CD4+ T-cells to become inducible Treg cells that act to block immune function. Dr. Young has demonstrated the origin of TAECs from normal endothelial cells. One potential approach to eliminate these tumor-induced, immune inhibitory mechanisms is to redirect the generation of progenitor immune cells by driving their differentiation into stimulatory dendritic cells (DCs) and to inhibit activity of TAECs by blocking their production of PGE2. Given the observation that TAECs produce PGE2, a study has been initiated at the HCC to treat newly diagnosed HNSCC patients with the combination of vitamin D3 and celecoxib prior to surgery and then evaluate cellular immune changes in the resected specimen, as shown in the figure.
This clinical study will be a follow up on a clinical trial arising out of Dr. Young’s earlier research and a clinical trial conducted by HCC physicians, Drs. Terry A. Day and M. Boyd Gillespie, in which HNSCC patients were treated weekly with vitamin D3 for three weeks from the time of diagnosis until surgery. Dr. Young’s observation that active metabolites of vitamin D3 drive the immune inhibitory CD34+ progenitor cells into DCs with functional antigen presenting capabilities stimulated this first clinical trial.
The results demonstrated diminished systemic levels of immune inhibitory progenitor cells and a simultaneous increase in the functional competence of peripheral blood T-cells, and this therapy was shown to improve recurrence-free survival. The new trial underway has the potential to suggest an expanded novel, non-toxic approach to stimulating the immune system and potentially increasing the response to known chemotherapeutic drugs in HNSCC.