Journal
BLOOD
Volume 111, Issue 1, Pages 229-235Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-05-089375
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Funding
- NATIONAL CANCER INSTITUTE [P50CA083636, R01CA104711] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000037] Funding Source: NIH RePORTER
- NCI NIH HHS [P50 CA083636, CA104711, R01 CA104711, CA 83636] Funding Source: Medline
- NCRR NIH HHS [MO1-RR-000037, M01 RR000037] Funding Source: Medline
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Efforts to reproducibly isolate tumor antigen-specific T cells from patients would be facilitated by removing immunoregulatory barriers. Using a human model for eliciting T-cell responses to tumor-associated antigens, we develop a novel strategy that eliminates nearly all Foxp3-expressing cells through the combination of CD25 depletion and IL-21 treatment resulting in a more than 150-fold decrease in Foxp3(+) cells to virtually undetectable levels and a more than 200-fold increase in antigen-specific cytotoxic T lymphocytes (CTLs). The extent of Foxp3 elimination and degree of expansion of antigen-specific CTLs shown in this study have not previously been achievable and are unique to IL-21. We demonstrate for the first time a possible mechanism for IL-21-mediated expansion of antigen-specific CTLs that involves suppression of Foxp3-expressing cells and reversal of inhibition to tumor-associated antigen-specific CTL generation in vitro. Taken together, the combination of CD25 depletion and IL-21 exposure, by releasing regulatory constraints, leads to markedly enhanced CTL induction and represents a robust strategy for the ex vivo generation of antigen-specific T cells for adoptive cellular therapy.
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