Increased serum transforming growth factor-beta1 in human colorectal cancer correlates with reduced circulating dendritic cells and increased colonic Langerhans cell infiltration

Abstract

Cancer-related cytokines may interfere with the differentiation and migration of dendritic cells (DCs) and with the associated up-regulation of co-stimulatory molecules in vitro. We determined whether cytokines affected the distribution and activation of DCs in patients with colorectal cancer by measuring the levels of serum cytokines [transforming growth factor (TGF)-beta1 and vascular endothelial growth factor (VEGF)], DC numbers and phenotype from peripheral blood and mesenteric lymph nodes draining the cancer, and the infiltration of DCs into colorectal cancer. A significant increase in the serum level of TGF-beta1 correlated with a significant reduction in the level of circulating DCs in cancer patients that was associated with an increased infiltration of Langerhans cells into colorectal mucosa. The prevalence but not intensity of co-stimulatory molecule expression in circulating and mesenteric lymph node DCs was reduced in patients with colorectal cancer compared to patients with inflammatory bowel conditions. There was no correlation between co-stimulatory molecule expression and serum TGF-beta1. Thus the circulating DC depletion in colorectal cancer could be explained by a TGF-beta1-related DC redistribution from the circulation into the colorectal cancer and adjacent mucosa where DC levels were increased. There was an impairment of DC activation within colorectal cancer that was not related to serum level of cytokines.

Fig. 1

Langerhans cells express CD1a and Langerin, whereas mature DCs express DC-LAMP.

Fig. 2

The level of circulating DCs increased at 6–8 weeks after primary tumour resection in colorectal patients without residual disease (Wilcoxon's signed rank test, n = 31, P = 0·0002) compared with those with residual disease (n = 10, P = 0·41) and with ‘no-cancer’ controls (n = 41, P = 0·94). Pre = preoperatively; Post = 6–8 weeks postoperatively; bars represent median and interquartile range. *Wilcoxon's signed rank test.

Fig. 3

There was a correlation between reduced circulating dendritic cells and an increased density of Langerhans cell infiltration (0 = 0 cells/high-power field, 1 = 1–5 cells/high-power field, 2 = 6–10 cells/high-power field and 3 = more than 10 cells/high-power field) of CD1a⁺ (anova test for linear contrast, P <0·0001, n = 44) and Langerin⁺ (P < 0·0001, n = 44) within the non-cancerous mucosa adjacent to colorectal cancer. One explanation for this is that a cancer-related increase in local levels of TGF-β1 resulted in DC redistribution from the circulation into the peri-tumoural tissues.

Fig. 4

Serum TGF-β1 correlated significantly with the level of circulating DCs in colorectal cancer patients (Spearman test, n = 33, r =−0·36, P = 0·04, 95% CI = −0·62 to –0·02) but not in control subjects (n = 33, r = 0·07, P = 0·70, 95% CI = −0·28–0·40).