Homeostasis of peripheral FoxP3(+) CD4 (+) regulatory T cells in patients with early and late stage breast cancer.
FoxP3( + ) CD4( + ) regulatory T cells (Tregs) are important mediators of peripheral immune tolerance, acting via multiple mechanisms to suppress cellular immunity including antitumor responses. Although therapeutic strategies have been proposed to deplete Tregs in patients with breast cancer and other malignancies, dynamic changes in the Treg compartment as a function of stage and treatment of breast cancer remain poorly understood. Here, we evaluated peripheral blood CD4(+) T cells and FoxP3(+) CD4(+) T cells from 45 patients with early or late stage breast cancer and compared percentages, absolute counts, and Treg function to those from healthy volunteers (HV) of comparable age. Patients having completed adjuvant chemotherapy and patients with metastatic cancer exhibited significantly lower absolute CD4 counts and significantly higher percentages of FoxP3(+) CD4(+) T cells. In contrast, the absolute counts of circulating FoxP3(+) CD4(+) T cells did not differ significantly among early stage patients, late stage patients, or HV. Functionally, FoxP3(+) CD4(+) T cells from all donor groups similarly expressed CTLA-4 and failed to secrete IFN-gamma in response to stimulation. Thus, although Tregs comprise an increased percentage of circulating CD4(+) T cells in patients with metastatic breast cancer and patients in remission after completing the adjuvant chemotherapy, the systemic Treg pool, as measured by absolute counts, appears relatively constant regardless of disease stage or treatment status. Total CD4(+) T cell counts are not constant, however, suggesting that homeostatic mechanisms, or susceptibility to cytotoxic or malignant insults, fundamentally differ for regulatory and non-regulatory CD4(+) T cells.
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 551 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA.
Andrew J
AJ
Rech
Rosemarie
R
Mick
David E
DE
Kaplan
Kyong-Mi
KM
Chang
Susan M
SM
Domchek
Robert H
RH
Vonderheide
D015703:Antigens, CD / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology* / Q000556:secondary; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D017024:Chemotherapy, Adjuvant; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma