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

• Published in: Blood Vol. 119; no. 24; pp. 5688 - 5696
• Main Authors: Yao, Xin, Ahmadzadeh, Mojgan, Lu, Yong-Chen, Liewehr, David J., Dudley, Mark E., Liu, Fang, Schrump, David S., Steinberg, Seth M., Rosenberg, Steven A., Robbins, Paul F.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 14.06.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Biological and medical sciences; CD4 Antigens - metabolism; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Dose-Response Relationship, Immunologic; Forkhead Transcription Factors - metabolism; Gene Therapy; Hematologic and hematopoietic diseases; Humans; Immunobiology; Immunotherapy, Adoptive - methods; Interleukin-2 - administration & dosage; Interleukin-2 - immunology; Lymphocyte Count; Lymphocytes, Tumor-Infiltrating - immunology; Medical sciences; Neoplasms - immunology; Neoplasms - therapy; Phenotype; T-Lymphocytes, Regulatory - immunology; Treatment Outcome; Whole-Body Irradiation; Human; Hematology; T-Lymphocyte; Malignant tumor; Adoptive immunization; Regulatory cell; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2011-10-386482

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.