Midgut carcinoid patients display increased numbers of regulatory T cells in peripheral blood with infiltration into tumor tissue.
BACKGROUND
Our aim was to investigate the immune status of midgut carcinoid patients. Cancer patients generally display suppressed Th1-type immunity that disables mounting of an efficient anti-tumor response. However, little is known about patients with neuroendocrine midgut carcinoids.


METHODS
Circulating regulatory T cells were determined in patient blood by staining for CD4, CD25 and FoxP3 in flow cytometric analysis. T cell proliferation was measured by Alamar Blue in response to polyclonal activation and the regulatory phenotype of patient CD25+ cells was validated by allogeneic stimulation of CFSE labelled responders. Cytokine levels in patient peripheral blood were measured by ELISA and CBA. Tumor infiltrating T cells were analyzed by immunohistochemistry and immunofluorescence.


RESULTS
The results demonstrate that midgut carcinoid patients exhibit increased frequencies of circulating Tregs and patient T cells have a decreased proliferative capacity compared to healthy donors. Systemic Th1-promoting cytokines are reduced. Midgut carcinoid tumors display CD4+ and CD8+ T cell infiltration, always in the presence of regulatory CD4+FoxP3+ cells.


CONCLUSIONS
Midgut carcinoid patients display elevated T regulatory cell numbers and T cell dysfunction. Therapeutic strategies to overcome tumor-induced Th1 immunosuppression are required in combination with anti-tumor vaccinations.
Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Sofia
S
Vikman
Roberta
R
Sommaggio
Manuel
M
De La Torre
Kjell
K
Oberg
Magnus
M
Essand
Valeria
V
Giandomenico
Angelica
A
Loskog
Thomas H
TH
Totterman
D015704:CD4 Antigens / Q000378:metabolism; D002276:Carcinoid Tumor / Q000097:blood* / Q000556:secondary; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms / Q000097:blood* / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood* / Q000556:secondary; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015704:CD4 Antigens; D016207:Cytokines