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Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer

2012; Elsevier BV; Volume: 119; Issue: 24 Linguagem: Inglês

10.1182/blood-2011-10-386482

1528-0020

Xin Yao, Mojgan Ahmadzadeh, Yong‐Chen Lu, David J. Liewehr, Mark E. Dudley, Fang Liu, David S. Schrump, Seth M. Steinberg, Steven A. Rosenberg, Paul F. Robbins,

CAR-T cell therapy research

CD4(+)FoxP3(+) regulatory T cells (Tregs) have been shown to suppress T cell-mediated host immune responses against self- and nonself-antigens; however, the impact of CD4(+) Tregs on human antitumor immune responses and their influence on cancer treatment are unknown. In the present study, we explored the factors that influence CD4(+) Treg reconstitution in patients receiving adoptive immunotherapy following conditioning regimens designed to enhance T-cell function and evaluated potential associations between CD4(+) Treg levels and clinical responses to therapy. The analysis of 4 trials employing nonmyeloablative chemotherapy with or without total body irradiation (TBI) before adoptive T-cell transfer revealed that the percentage and number of reconstituting CD4(+)FoxP3(+) Tregs observed in the peripheral blood was higher in nonresponders than in responders. The addition of TBI resulted in a further depletion of CD4(+) Tregs, and the degree of depletion was dependent on the TBI dose. The number of administered doses of IL-2 was found to be positively associated with peripheral Treg reconstitution. These observations provide strong evidence that endogenous CD4(+) Tregs have a negative impact on cancer therapy, and suggest that strategies reducing Treg levels may provide clinical benefit to cancer patients. All 5 clinical trials are registered at www.clinicaltrials.gov as NCT00001832, NCT00096382, NCT00335127, NCT00509496, and NCT00513604.