Inhibition of dendritic cell maturation by the tumor microenvironment correlates with the survival of colorectal cancer patients following bevacizumab treatment.

Development of bevacizumab has improved survival in colorectal cancer, however, currently there are no biomarkers that predict response to bevacizumab and it is unknown how it influences the immune system in colorectal cancer patients. Dendritic cells are important for the induction of an antitumor immune response; however tumors are capable of disabling dendritic cells and escaping immune surveillance. The aim of this study was to assess the numbers of CD11c+ cells infiltrating tumor tissue and to examine the effects of tumor conditioned media (TCM) and bevacizumab conditioned media (BCM) on dendritic cell maturation and correlate our findings with patient survival. colorectal cancer explant tissues were cultured with or without bevacizumab, to generate BCM and TCM, which were used to treat dendritic cells. CD80, CD86, CD83, CD54, HLA-DR, and CD1d expression was measured by flow cytometry. Interleukin (IL)-10 and IL-12p70 were measured by ELISA. The Cox proportional hazards model was used to associate survival with dendritic cell inhibition. TCM and BCM inhibited lipopolysaccharide (LPS)-induced dendritic cell maturation and IL-12p70 secretion (P < 0.0001), while increasing IL-10 secretion (P = 0.0033 and 0.0220, respectively). Inhibition of LPS-induced CD1d (P = 0.021, HR = 1.096) and CD83 (P = 0.017, HR = 1.083) by TCM and inhibition of CD1d (P = 0.017, HR = 1.067), CD83 (P = 0.032, HR = 1.035), and IL-12p70 (P = 0.037, HR = 1.036) by BCM was associated with poor survival in colorectal cancer patients. CD11c expression was elevated in tumor tissue compared with normal tissue (P < 0.001), but this did not correlate with survival. In conclusion, TCM and BCM inhibit dendritic cells, and this inhibition correlates with survival of colorectal cancer patients receiving bevacizumab.

Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.

Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5) could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.

Collagenous sprue: a clinicopathologic study of 12 cases.

Collagenous sprue is a rare form of small bowel enteropathy characterized by chronic diarrhea and progressive malabsorption with little data available on its natural history. The pathologic lesion consists of subepithelial collagen deposition associated with variable alterations in villous architecture. The small bowel biopsies of 12 cases were reviewed. Clinical details, celiac serology, and T-cell receptor gene rearrangement study results, when available, were collated. There were 8 females and 4 males (age ranged from 41 to 84 y) who presented with chronic diarrhea and weight loss. Small intestinal biopsies showed subepithelial collagen deposition with varying degrees of villous atrophy and varying numbers of intraepithelial lymphocytes. Four patients had previous biopsies showing enteropathic changes without collagen deposition. Seven cases were associated with collagenous colitis and 1 also had features of lymphocytic colitis. Three patients also had collagen deposition in gastric biopsies. One case was associated with lymphocytic gastritis. Celiac disease (CD, gluten-sensitive enteropathy) was documented in 4 patients. Five patients made a clinical improvement with combinations of a gluten-free diet and immunosuppressive therapy. Two patients died of complications of malnutrition and 1 of another illness. Clonal T-cell populations were identified in 5 of 6 cases tested. Four of these patients improved clinically after treatment but 1 has died. Collagenous sprue evolved on a background of CD in 4 cases. There was no history of CD in others and these cases may be the result of a biologic insult other than gluten sensitivity. None has developed clinical evidence of lymphoma to date.