Inhibition of Dendritic Cell Maturation by the Tumor Microenvironment Correlates with the Survival of Colorectal Cancer Patients following Bevacizumab Treatment

Michielsen, Adriana J.; Noonan, Sinéad; Martin, Petra; Tosetto, Miriam; Marry, Joseph; Biniecka, Monika; Maguire, Aoife; Hyland, John; Sheahan, Kieran; O’Donoghue, Diarmuid; Mulcahy, Hugh; Fennelly, D.; Ryan, Elizabeth J.; O'Sullivan, Jacintha

doi:10.1158/1535-7163.mct-12-0162

Cited by 35 publications

(37 citation statements)

References 33 publications

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“…Nevertheless, our data show that the proper function of a comprehensive network of immune response genes is of vital importance for the survival of colorectal cancer patients. Recent results indicating that the tumor microenvironment can reduce the maturation of dendritic cells [49,50] hint to the importance of our findings and suggest avenues for prognosis and treatment.…”

Section: Discussionmentioning

confidence: 59%

Concerted down-regulation of immune-system related genes predicts metastasis in colorectal carcinoma

et al. 2014

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BackgroundThis study aimed at the identification of prognostic gene expression markers in early primary colorectal carcinomas without metastasis at the time point of surgery by analyzing genome-wide gene expression profiles using oligonucleotide microarrays.MethodsCryo-conserved tumor specimens from 45 patients with early colorectal cancers were examined, with the majority of them being UICC stage II or earlier and with a follow-up time of 41–115 months. Gene expression profiling was performed using Whole Human Genome 4x44K Oligonucleotide Microarrays. Validation of microarray data was performed on five of the genes in a smaller cohort.ResultsUsing a novel algorithm based on the recursive application of support vector machines (SVMs), we selected a signature of 44 probes that discriminated between patients developing later metastasis and patients with a good prognosis. Interestingly, almost half of the genes was related to the patients’ immune response and showed reduced expression in the metastatic cases.ConclusionsWhereas up to now gene signatures containing genes with various biological functions have been described for prediction of metastasis in CRC, in this study metastasis could be well predicted by a set of gene expression markers consisting exclusively of genes related to the MHC class II complex involved in immune response. Thus, our data emphasize that the proper function of a comprehensive network of immune response genes is of vital importance for the survival of colorectal cancer patients.

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Section: Discussionmentioning

confidence: 59%

Concerted down-regulation of immune-system related genes predicts metastasis in colorectal carcinoma

et al. 2014

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“…Indeed, esophageal epithelial cells expressing HLA-DR have been shown to have functional ability and can effectively process and present antigens to T cells [12]. Therefore, it is possible that HLA-DR upregulation by tumor epithelial cells plays a direct functional role in anti-tumor immunity, potentially acting as a compensatory mechanism for tumor-induced inhibition of professional antigen-presenting cells such as dendritic cells, as previously shown by our group in colorectal cancer [32]. …”

Section: Discussionmentioning

confidence: 81%

HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients

Dunne

Michielsen

O’Sullivan

et al. 2017

Cancer Immunol Immunother

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Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis, and incidence is increasing rapidly in the Western world. Measurement of immune markers has been shown to have prognostic significance in a growing number of cancers, but whether this is true for EAC has yet to be evaluated. This study aimed to characterize HLA-DR expression in the esophagus across the inflammation to cancer progression sequence and to assess the prognostic significance of HLA-DR expression in EAC. Tissue microarrays (TMA) were constructed from esophageal tissue taken from patients at different stages in the cancer progression sequence; normal, esophagitis, Barrett’s esophagus (BE), low- and high-grade dysplasia (LGD, HGD) and EAC. HLA-DR expression in tissue epithelium and stroma was assessed by immunohistochemistry. HLA-DR expression increased early in the inflammation to cancer progression sequence; with higher expression detected in esophagitis and BE compared to normal tissue. Patients with low (<50%) HLA-DR expression in the EAC tumor epithelium had significantly worse survival outcomes, compared to those with high expression, in both the tumor core (hazard ratio, HR = 2.178, p = 0.024, n = 70) and leading edge (HR = 2.86, p = 0.013, n = 41). Multivariate analysis demonstrated that low HLA-DR expression in leading edge tumor epithelium was an independent predictor of poor survival, associated with a 2.8-fold increase in disease-associated death (p = 0.023). This study shows that HLA-DR is an independent prognostic marker in EAC tumor epithelium. This may have implications for patient stratification strategies as well as EAC tumor immunology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-017-1983-1) contains supplementary material, which is available to authorized users.

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“…We have previously demonstrated that the TME of advanced colorectal cancer (CRC) suppresses monocyte-derived dendritic cell (MDDC) maturation and IL-12p70 secretion (Michielsen et al , 2011). Importantly, the degree of this inhibition correlated with the survival of stage IV patients receiving bevacizumab therapy (Michielsen et al , 2012). Although changes in DC phenotype have been noted in both colorectal (Gulubova et al , 2012) and ovarian (Scarlett et al , 2012) cancer progression, it is not clear if the immunosuppressive nature of the TME varies with disease progression in colorectal cancer.…”

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confidence: 99%

“…Here we used our established tumour explant model (Michielsen et al , 2011, 2012) to determine if the microenvironment of earlier staged tumours is as suppressive as that of patients with metastatic disease. In addition we characterised the phenotype of non-metastatic CRC patients' MDDCs and examined production of IL-12p70 in response to lipopolysaccharide (LPS) in both the absence and presence of tumour-conditioned media.…”

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confidence: 99%

Tumour microenvironment of both early- and late-stage colorectal cancer is equally immunosuppressive

et al. 2014

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BackgroundTumour microenvironment (TME) of advanced colorectal cancer (CRC) suppresses dendritic cell (DC) maturation. Here, our aim was to determine how the microenvironment of early-stage tumours influences DCs.Methods:Tumour-conditioned media (TCM) was generated by culturing explant tumour tissue in vitro (n=50). Monocyte-derived DCs (MDDCs) of healthy donors or cancer patients were pretreated with TCM and stimulated with lipopolysaccharide (LPS). DC maturation was assessed by flow cytometry and cytokine production measured by ELISA.Results:TCM from both early- and late-staged tumours abrogated LPS-induction of IL-12p70 secretion, while increasing IL-10. The profile of inflammatory mediators in TCM was similar across stages, and all increased pSTAT3 expression by DCs.CRC patient DCs (n=31) secreted low levels of IL-12p70 and failed to upregulate expression of maturation markers in response to LPS. Furthermore, in vitro culture of autologous DCs with TCM did not change the hypo-responsiveness of patient DCs.Conclusion:Our data demonstrates that the TME of all stages of CRC contains inflammatory mediators capable of suppressing local DCs. MDDCs obtained from CRC patients are hyporesponsive to stimuli such as LPS. Measures to reverse the negative influence of the TME on DCs will optimise cancer vaccines in both early- and late-stage CRC.

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Inhibition of Dendritic Cell Maturation by the Tumor Microenvironment Correlates with the Survival of Colorectal Cancer Patients following Bevacizumab Treatment

Cited by 35 publications

References 33 publications

Concerted down-regulation of immune-system related genes predicts metastasis in colorectal carcinoma

Concerted down-regulation of immune-system related genes predicts metastasis in colorectal carcinoma

HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients

Tumour microenvironment of both early- and late-stage colorectal cancer is equally immunosuppressive

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