title: Reduction in cytokine production in colorectal cancer patients: association with stage and reversal by resection.
abstract: The aim of this study was to assess monocyte/macrophage function, as defined by lipopolysaccharide (LPS)-induced production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-10 and interferon (IFN)-gamma by stimulated whole blood cultures in patients with colorectal carcinoma before and after surgical resection. Forty colorectal cancer patients prior to surgery and 31 healthy controls were studied. Heparinized venous blood was taken from colorectal cancer patients prior to surgery and from healthy controls. Serial samples were obtained at least 3-6 weeks post-operatively. Blood was stimulated with LPS for 24 h and supernatants were assayed for TNF-alpha, IFN-gamma and IL-10 by enzyme-linked immunosorbent assay. LPS-induced production of TNF-alpha and of IFN-gamma was reduced in patients with colorectal carcinoma compared to controls (TNF-alpha, 11,269 pg/ml(-1) ¿12,598¿; IFN-gamma, 0.00 pg/ml(-1) ¿226¿; median ¿IQR¿) (TNF-alpha, 20,576 pg/m(-1) ¿11,637¿, P < 0.0001; IFN-gamma, 1,048 ¿2,428¿, P = 0.0051, Mann-Whitney U-test). Production in patients after surgery had increased (TNF-alpha: 17,620 pg/ml(-1) ¿7,986¿; IFN-gamma. 410 pg/ml(-1) ¿2,696¿; mean ¿s.d.¿) and were no longer significantly reduced when compared to controls (TNF-alpha, P = 0.28; IFN-gamma, P = 0.76). Production of TNF-alpha and IFN-gamma prior to surgery were reduced to a greater extent in patients with Dukes' stage C tumours compared to those with Dukes' stage A and B stage. There was no difference in IL-10 production between any group. Monocytes/macrophages from patients with colorectal carcinoma are refractory to LPS stimulation as reflected by reduction in TNF-alpha and IFN-gamma production and this is more pronounced in patients with advanced stage tumours. This suppression is not mediated by IL-10 and disappears following surgical resection of the tumour. This provides evidence for tumour induced suppression of immune function in patients with colorectal cancer and identifies a potential therapeutic avenue.
authors.affiliation: Colorectal Surgery Unit, St. George's Hospital Medical School, London, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Heriot
authors.forename: J B
authors.initials: JB
authors.lastname: Marriott
authors.forename: S
authors.initials: S
authors.lastname: Cookson
authors.forename: D
authors.initials: D
authors.lastname: Kumar
authors.forename: A G
authors.initials: AG
authors.lastname: Dalgleish
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000601:surgery; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D008297:Male; D009000:Monocytes / Q000502:physiology*; D009367:Neoplasm Staging; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma