Myeloid-derived suppressor cells (MDSCs) represent heterogeneous immunosuppressive cells in multiple cancer types and display potent immunosuppressive activity on T cells. We have shown the increased expression of IDO in breast cancer. Because IDO plays a pivotal role in immune tolerance via suppressing T cell function, the aim of this study was to investigate the expression of IDO in MDSCs in breast cancer and its role in MDSC-mediated inhibition of immune surveillance. The proportion of MDSCs with the phenotype of CD45+CD13+CD33+CD14−CD15− significantly increased in primary cancer tissues and patients’ peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3+ regulatory T cells in tumors and lymph node metastasis in patients. fMDSCs inhibited IL-2 and anti-CD3/CD28 mAb-induced T cell amplification and Th1 polarization but stimulated apoptosis in T cells in an IDO-dependent manner. CD33+ progenitors isolated from healthy donors’ umbilical cord blood were cocultured with breast cancer cell line MDA-MB-231 cells to induce MDSCs. IDO expression was upregulated in induced MDSCs, which required phosphorylation of STAT3, but not STAT1. IDO was required for induced MDSCs’ immunosuppressive activity on T cells, which was blocked by IDO inhibitor 1-methyl-L-tryptophan or STAT3 antagonist JSI-124. Consistently, increased STAT3 phosphorylation level was found in fMDSCs. Together, our findings suggest that STAT3-dependent IDO expression mediates immunosuppressive effects of MDSCs in breast cancer. Thus, inhibition of MDSC-induced T cell suppression by blocking IDO may represent a previously unrecognized mechanism underlying immunotherapy for breast cancer.
BackgroundFecal microbiota transplantation (FMT) is a microbiota-based therapy that shows therapeutic potential in recurrent or refractory Clostridium difficile infections and other intestinal or extra-intestinal disorders. Nonetheless, adverse events (AEs) remain a major challenge in the application of FMT.AimTo review the AEs of FMT and to address the concerns of safety during the procedure.MethodsPublications were retrieved in the databases of Medline, Embase and Cochrane Library. AEs were classified according to their causality with FMT or their severity.ResultsA total of 7562 original articles about FMT were identified in this study, 50 of them fulfilled the inclusion criteria. Totally 78 kinds of AEs were revealed enrolled in these 50 selected publications. The total incidence rate of AEs was 28.5%. Among the 42 publications, 5 kinds were definitely and 38 kinds were probably related to FMT. The commonest FMT-attributable AE was abdominal discomfort, which was reported in 19 publications. For upper gastrointestinal routes of FMT, 43.6% (89/204) patients were compromised by FMT-attributable AE, while the incidence dropped to 17.7% (76/430) for lower gastrointestinal routes. In contrast, the incidences of serious adverse events (SAEs) were 2.0% (4/196) and 6.1% (40/659) for upper and lower gastrointestinal routes, respectively. A total of 44 kinds of SAEs occurred in 9.2% patients, including death (3.5%, 38/1089), infection (2.5%, 27/1089), relapse of inflammatory bowel diseases (0.6%, 7/1089) and Clostridium difficile infection (0.9%, 10/1089).ConclusionConsequently, both AEs and SAEs are not rare and should be carefully monitored throughout FMT. However, high quality randomized controlled trials are still needed for the more definite incidence of AEs of FMT.
Amplification of 1q21 is the most frequent genetic alteration in human hepatocellular carcinoma (HCC), being detected in 58%-78% of primary HCC cases by comparative genomic hybridization. Recently, we isolated a candidate oncogene, Amplified in Liver Cancer 1 (ALC1), from 1q21 by hybrid selection. Here we demonstrate that ALC1 was frequently amplified and overexpressed in HCC. ALC1-transfected cells possessed a strong oncogenic ability, increasing the colony formation in soft agar and increasing the tumorigenicity in nude mice, which could be effectively suppressed by small interfering RNA against ALC1. Functional studies showed that overexpression of ALC1 could promote G1/S phase transition and inhibit apoptosis. Molecular studies revealed that the oncogenic function of ALC1 might be associated with its roles in promoting cell proliferation by down-regulating p53 expression. Conclusion: These results suggest that ALC1 is the target oncogene within the 1q21 amplicon and plays a pivotal role in HCC pathogenesis. (HEPATOLOGY 2008;47:503-510.)
Intestinal dysbiosis is now known to be a complication in a myriad of diseases. Fecal microbiota transplantation (FMT), as a microbiota-target therapy, is arguably very effective for curing Clostridium difficile infection and has good outcomes in other intestinal diseases. New insights have raised an interest in FMT for the management of extra-intestinal disorders associated with gut microbiota. This review shows that it is an exciting time in the burgeoning science of FMT application in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors. A randomized controlled trial was conducted on FMT in metabolic syndrome by infusing microbiota from lean donors or from self-collected feces, with the resultant findings showing that the lean donor feces group displayed increased insulin sensitivity, along with increased levels of butyrate-producing intestinal microbiota. Case reports of FMT have also shown favorable outcomes in Parkinson's disease, multiple sclerosis, myoclonus dystonia, chronic fatigue syndrome, and idiopathic thrombocytopenic purpura. FMT is a promising approach in the manipulation of the intestinal microbiota and has potential applications in a variety of extra-intestinal conditions associated with intestinal dysbiosis.
Immunotherapy exerts anticancer effects by activating competent immune effectors and inhibiting immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). However, the mechanism underlying MDSCs-mediated immunosuppression in breast cancer is unclear. We have identified a poorly differentiated subset of MDSCs in breast cancer, which suppresses T-cell functions through STAT3-dependent IDO upregulation. Here, we aimed to investigate the mechanisms by which IDO expression is aberrant in MDSCs. We found increased STAT3 phosphorylation and NIK expression were correlated with upregulated IDO expression in MDSCs in human breast cancer. In mouse 4T1 mammary cancer model, blocking STAT3 signal significantly inhibited the activation of NF-κB and IDO expression in MDSCs, resulting in decrease of tumor growth and metastasis. We also induced MDSCs by co-culturing human CD33+ myeloid progenitors with MDA-MB-231 breast cancer cells. In these induced MDSCs, increased STAT3 activation was correlated with the activation of the noncanonical NF-κB pathway, including increased NIK protein level, phosphorylation of IKKα and p100 in cytoplasm, and RelB-p52 nuclear translocation. Blocking STAT3 activation significantly inhibited the accumulation of NIK and IDO expression in MDSCs. Knock-down of NIK by siRNA transfection in MDSCs suppressed IDO expression, but not STAT3 activation. Transcription factor assay and ChIP assay showed that RelB-p52 dimers directly bound to the IDO promoter, leading to IDO expression in MDSCs. These results suggest a STAT3-NF-κB-IDO pathway in breast cancer-derived MDSCs. Furthermore, IL-6 was found to stimulate STAT3-dependent NF-κB-mediated IDO upregulation in MDSCs. This study provides insights into understanding mechanisms through which MDSCs play an immunosuppressive role in breast cancer.
Using oligonucleotide microarray analysis, THY1, mapping close to a previously defined 11q22-23 nasopharyngeal carcinoma (NPC) critical region was identified as showing consistent downregulated expression in the tumour segregants, as compared to their parental tumour-suppressing microcell hybrids (MCHs). Gene expression and protein analyses show that THY1 was not expressed in the NPC HONE1 recipient cells, tumour segregants, and other NPC cell lines; THY1 was exclusively expressed in the non-tumourigenic MCHs. The mechanism of THY1 gene inactivation in these cell lines was attributed to hypermethylation. Clinical study showed that in 65% of NPC specimens there was either downregulation or loss of THY1 gene expression. Using a tissue microarray and immunohistochemical staining, 44% of the NPC cases showed downregulated expression of THY1 and 9% lost THY1 expression. The frequency of THY1 downregulated expression in lymph node metastatic NPC was 63%, which was significantly higher than in the primary tumour (33%). After transfection of THY1 gene into HONE1 cells, a dramatic reduction of colony formation ability was observed. These findings suggest that THY1 is a good candidate tumour suppressor gene in NPC, which is significantly associated with lymph node metastases.
Amplification of 3q26 is one of the most frequent chromosomal alterations in many solid tumors, including ovarian, lung, esophageal, prostate, breast, and nasopharyngeal cancers. A candidate oncogene to eukaryotic initiation factor 5A2 (eIF-5A2), a member of eukaryotic initiation factor 5A subfamily, has been isolated from a frequently amplified region at 3q26.2. In this work, the tumorigenic ability of eIF-5A2 was demonstrated by anchorage-independent growth in soft agar and tumor formation in nude mice. Furthermore, antisense DNA against eIF-5A2 could inhibit cell growth in ovarian cancer cell line UACC-1598 with amplification of eIF-5A2 in form of double minutes. Cell growth rate in UACC-1598 was also inhibited when the expression level of EIF-5A2 was decreased by the reduction of the copy number of double minutes. The correlation of EIF-5A2 overexpression and clinical features of ovarian cancer was investigated using tissue microarray, and the result showed that eIF-5A2 overexpression was significantly associated with the advanced stage of ovarian cancer. These findings suggest that eIF-5A2 plays important roles in ovarian pathogenesis.
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