title: The effects of trastuzumab on the CD4+CD25+FoxP3+ and CD4+IL17A+ T-cell axis in patients with breast cancer.
abstract: In addition to the direct targeting effects on HER2-positive cells, trastuzumab may have a therapeutic role modulating the activity of the cellular immune system in patients with breast cancer. To investigate this further, the balance of T-regulatory (T(reg)), Th17, natural killer (NK) and NK T (NKT) cells before, during and after trastuzumab therapy was investigated. Sequential frequencies of circulating T(reg) cells, Th17 cells, NK and NKT cells were measured in peripheral blood of breast cancer patients and normal controls throughout therapy. Individuals with breast cancer had significantly higher T(reg) frequencies of peripheral blood compared with healthy controls (9.2 or 8.6 vs 6%; P<0.05), and no significant differences in T(reg) frequencies were observed between HER2-positive and HER2-negative individuals. The number of Th17 cells was lowest in HER2-positive patients compared with both healthy controls and HER2-negative patients (0.31 vs 0.75% or 0.84%; P=0.01). There appeared to be an inverse relationship between T(reg) and Th17 frequencies in metastatic breast cancer (MBC) with T(reg) levels significantly reduced during treatment with trastuzumab (P=0.04), whereas Th17 frequencies were concomitantly increased (P=0.04). This study supports earlier data that T(reg) cells are present at higher frequencies in breast cancer patients compared with healthy individuals. For the first time, we show that HER2-positive individuals with breast carcinomas have reduced numbers of circulating Th17 cells, which appear, in turn to have an inverse relationship with T(reg) frequency in MBC. The change in balance of the T(reg) : Th17 ratio appears to characterise the cancer state, and furthermore, is disrupted by trastuzumab therapy.
authors.affiliation: Department of Oncology, Imperial College School of Medicine, Hammersmith Hospital Campus, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Horlock
authors.forename: B
authors.initials: B
authors.lastname: Stott
authors.forename: P J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: M
authors.initials: M
authors.lastname: Morishita
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
authors.forename: P
authors.initials: P
authors.lastname: Savage
authors.forename: J
authors.initials: J
authors.lastname: Stebbing
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D020381:Interleukin-17 / Q000032:analysis*; D007694:Killer Cells, Natural / Q000276:immunology; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C418974:FOXP3 protein, human; C508717:IL17A protein, human; C508053:ERBB2 protein, human