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Blood, 15 December 2008, Vol. 112, No. 13, pp. 4953-4960.
Prepublished online as a Blood First Edition Paper on September 26, 2008; DOI 10.1182/blood-2008-06-163048.
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Submitted June 17, 2008
Accepted September 8, 2008
FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions
Mojgan Ahmadzadeh*, Aloisio Felipe-Silva, Bianca Heemskerk, Daniel J Powell Jr, John R Wunderlich, Maria J Merino, and Steven A. Rosenberg
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD, United States
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD, United States
* Corresponding author; email: mojgan_ahmadzadeh{at}nih.gov.
Regulatory T cells (Treg) are often found in human tumors; however, their functional characteristics have been difficult to evaluate due to low cell number and the inability to adequately distinguish between activated and regulatory T cell populations. Using a novel approach, we examined the intracellular cytokine production capacity of tumor infiltrating T cells in the single cell suspensions of enzymatically-digested tumors to differentiate Treg from effector T cells. Similar to Treg in the peripheral blood of healthy individuals, tumor infiltrating FOXP3+CD4 T cells, unlike FOXP3- T cells, were unable to produce IL-2 and IFN- upon ex vivo stimulation, indicating that FOXP3 expression is a valid biological marker for human Treg even in the tumor microenvironment. Accordingly, we enumerated FOXP3+CD4 Treg in intratumoral and peritumoral sections of metastatic melanoma tumors and found a significant increase in proportion of FOXP3+CD4 Treg in the intratumoral compared to peritumoral areas. Moreover, their frequencies were three- to five-fold higher in tumors than in peripheral blood of matched patients or healthy donors, respectively. These findings demonstrate that the tumor infiltrating CD4 Treg population is accurately depicted by FOXP3 expression, they selectively accumulate in tumors, and their frequencies in peripheral blood does not properly reflect tumor microenvironment.
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