title: Regulatory T-cell-mediated inhibition of antitumor immune responses is associated with clinical outcome in patients with liver metastasis from colorectal cancer.
abstract: Adaptive regulatory T cells (Tregs) contribute to an immunosuppressive microenvironment in colorectal cancer (CRC). Here, we examined whether the level of Treg-mediated inhibition of antitumor immune responses in patients with metastatic CRC (metCRC) selected for liver resection is associated with clinical outcome. Preoperatively and at follow-ups, we did flow-based phenotyping, examined antitumor immunity using peptides from carcinoembryonic antigen (CEA) protein in the presence or absence of CD4(+)CD25(+)CD127(dim/-) cells (Tregs) and determined cytokine and PGE(2) levels in patient blood samples. At 18 months post-surgery, 8 patients were disease free (7 alive and 1 dead of unrelated cause) and 10 had experienced disease recurrence (7 alive and 3 dead of metCRC). Prior to surgery, the patients demonstrated Treg-mediated suppression of TNFα and IFNγ expression that could be perturbed through the PGE(2)/cAMP pathway and the immune suppression was significantly higher in the group that later developed disease recurrence (P = 0.046). Furthermore, the post-surgery plasma PGE(2) levels were related to the clinical outcome (PGE(2) levels of 280 ± 47 vs. 704 ± 153 pg/ml (mean ± SEM) for disease free and recurrent disease, respectively). T-cell phenotyping revealed higher frequencies of COX-2(+) cells in the patients with recurrent disease. These findings support the notion that the level of Treg-mediated suppression of adaptive antitumor immune responses at the time of surgery may influence later clinical outcome of metCRC and provide valuable prognostic information.
authors.affiliation: Centre for Molecular Medicine Norway, University of Oslo, Blindern, Norway.
authors.forename: Kristoffer Watten
authors.initials: KW
authors.lastname: Brudvik
authors.forename: Karen
authors.initials: K
authors.lastname: Henjum
authors.forename: Einar Martin
authors.initials: EM
authors.lastname: Aandahl
authors.forename: Bjørn Atle
authors.initials: BA
authors.lastname: Bjørnbeth
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016207:Cytokines / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary* / Q000601:surgery; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D051546:Cyclooxygenase 2; D015232:Dinoprostone