Midgut carcinoid patients display increased numbers of regulatory T cells in peripheral blood with infiltration into tumor tissue

Abstract

Introduction.Our aim was to investigate the immune status of midgut carcinoid patients. Cancer patients generally displaysuppressed Th1-type immunity that disables mounting of an efficient anti-tumor response. However, little is known aboutpatients with neuroendocrine midgut carcinoids.Material and methods.Circulating regulatory T cells were determined inpatient blood by staining for CD4, CD25 and FoxP3 in flow cytometric analysis. T cell proliferation was measured byAlamar Blue in response to polyclonal activation and the regulatory phenotype of patient CD25cells was validated byallogeneic stimulation of CFSE labelled responders. Cytokine levels in patient peripheral blood were measured by ELISAand CBA. Tumor infiltrating T cells were analyzed by immunohistochemistry and immunofluorescence.Results.The resultsdemonstrate that midgut carcinoid patients exhibit increased frequencies of circulating Tregs and patient T cells have adecreased proliferative capacity compared to healthy donors. Systemic Th1-promoting cytokines are reduced. Midgutcarcinoid tumors display CD4and CD8T cell infiltration, always in the presence of regulatory CD4FoxP3cells.Discussion.Midgut carcinoid patients display elevated T regulatory cell numbers and T cell dysfunction. Therapeuticstrategies to overcome tumor-induced Th1 immunosuppression are required in combination with anti-tumor vaccinations.