Impaired interleukin-12 production is associated with a defective anti-tumor response in colorectal cancer

O'Hara, Richard; Greenman, John; Drew, Philip; McDonald, Alistair W.; Duthie, G. S.; Lee, Peter W. R.; Monson, J. R. T.

doi:10.1007/bf02235759

Cited by 17 publications

(8 citation statements)

References 14 publications

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“…In fact, as CRC metastases were each all located in liver, an improvement in sCD26 levels should be expected, as well as a correlation with the kind of metastasis. However, a cross-talk between the lymphoid lineage and malignant tumours in vivo have been long discussed (Shibuya-Saruta et al, 1996;Gruss et al, 1997;Nano et al, 1997;Iwata and Morimoto, 1999) and some data about the immune defective antitumour response in CRC have been described before, including a defect in IL-12 production (O'Hara et al, 1998), which is a well-known CD26 up-regulator (Cordero et al, 1997) on T cells. In oral cancer patients, in which around a 50% decrease in serum DPP-IV activity has been reported, a correlation between sCD26 and CD26+ T was found, and the number of T lymphocytes and PBL and the amount of CD26 in T lymphocyte plasma membranes were significantly less than in healthy subjects (Uematsu et al, 1996;.…”

Section: Discussionmentioning

confidence: 99%

Preoperative serum CD26 levels: diagnostic efficiency and predictive value for colorectal cancer

et al. 2000

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CD26 is an ectoenzyme with dipeptidyl peptidase IV activity expressed on a variety of cell types. Although the function of the high concentration of serum-soluble CD26 (sCD26) is unknown, it may be related to the cleavage of biologically active polypeptides. As CD26 or enzymatic activity levels were previously associated with cancer, we examined the potential diagnostic and prognostic value of preoperative sCD26 measurements by ELISA in colorectal carcinoma patients. We found a highly significant difference between sCD26 levels in healthy donors (mean 559.7 ± 125.5 μg l –1 ) and cancer patients (mean 261.7 ± 138.1 μg l –1 ) ( P < 0.001). A cut-off at 410 μg l –1 gave 90% sensitivity with 90% specificity which means that the diagnostic efficiency of sCD26 is higher than that shown by other markers, particularly in patients at early stages. Moreover, sCD26 as a variable is not related with Dukes’ stage classification, age, gender, tumour location or degree of differentiation. With a follow-up of 2 years until recurrence, preliminary data show that sCD26 can be managed as a prognostic variable of early carcinoma patients. In addition, the origin of sCD26 is discussed. © 2000 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 99%

Preoperative serum CD26 levels: diagnostic efficiency and predictive value for colorectal cancer

et al. 2000

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“…IFN-γ is also crucial for the induction of IL-12 which is a powerful inducer of Th-1 type immunity and an important cytokine in the generation of anti-tumour immunity. Interestingly, a recent study by O'Hara et al (1998) has demonstrated that the production of IL-12 is deficient in patients with colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Reduction in cytokine production in colorectal cancer patients: association with stage and reversal by resection

Heriot¹,

Marriott

Cookson

et al. 2000

Br J Cancer

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SummaryThe aim of this study was to assess monocyte/macrophage function, as defined by lipopolysaccharide (LPS)-induced production of tumour necrosis factor (TNF)-α, interleukin (IL)-10 and interferon (IFN)-γ 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-α, IFN-γ and IL-10 by enzyme-linked immunosorbent assay. LPS-induced production of TNF-α and of IFN-γ was reduced in patients with colorectal carcinoma compared to controls (TNF-α, 11 269 pg ml -1 {12 598}; IFN-γ, 0.00 pg ml -1 {226}; median {IQR}) (TNF-α, 20 576 pg ml -1 {11 637}, P < 0.0001; IFN-γ, 1048 {2428}, P = 0.0051, Mann-Whitney U-test). Production in patients after surgery had increased (TNF-α: 17 620 pg ml -1 {7986}; IFN-γ: 410 pg ml -1 {2696}; mean {s.d.}) and were no longer significantly reduced when compared to controls (TNF-α, P = 0.28; IFN-γ, P = 0.76). Production of TNF-α and IFN-γ 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-α and IFN-γ 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.

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“…27,57,58 Some studies have documented impaired production of IL-12 in patients with a variety of malignancies, and this appears to be associated with an impaired T-helper cell 1 (Th1)-mediated tumor response and to correlate with extent of disease. 59,60 In animal models, IL-12-secreting tumor vaccines have been shown to cause regression of established tumors and to suppress the growth of parental tumor cells. 25,27 Further, Rakhmilevich et al, 61 using gene gun technology, transfected dermal tumors with a variety of immunostimulatory cytokine genes and found that IL-12 was the most effective in causing tumor regression and was the only cytokine investigated that was capable of causing tumor regression at distant sites.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant Interleukin-12 Immunogene Therapy Protects Against Cancer Recurrence After Liver Resection in an Animal Model

Jarnagin¹,

Delman²,

Kooby³

et al. 2000

Annals of Surgery

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Impaired interleukin-12 production is associated with a defective anti-tumor response in colorectal cancer

Abstract: Interleukin-12 production is impaired in patients with colorectal cancer, especially those with advanced disease, suggesting a defective Thl-mediated anti-tumor response. These patients may well benefit from exogenous interleukin-12 treatment.

Cited by 17 publications

References 14 publications

Preoperative serum CD26 levels: diagnostic efficiency and predictive value for colorectal cancer

Preoperative serum CD26 levels: diagnostic efficiency and predictive value for colorectal cancer

Reduction in cytokine production in colorectal cancer patients: association with stage and reversal by resection

Neoadjuvant Interleukin-12 Immunogene Therapy Protects Against Cancer Recurrence After Liver Resection in an Animal Model

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