Expression profiles and function of IL6 in polymorphonuclear myeloid-derived suppressor cells

We report here that colonic inflammation induces IL6 expression primarily in the CD11b+Ly6G+Ly6Clo polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in colon. Although both tumor cells, T cells and myeloid cells all express IL6, PMN-MDSCs are the primary cell type that express IL6 in colon carcinoma, suggesting that IL6 up-regulation is a response to inflammation in colon epithelium and tumor microenvironment. Furthermore, we determined that IL6 activates STAT3 to up-regulate DNMT1 and DNMT3b expression in colon tumor cells, thereby revealing an epigenetic mechanism that mediates the IL6-STAT3 signaling pathway in colon carcinoma. Surprisingly, knocking out IL6 in colon tumor cells did not significantly alter tumor growth in WT mice. Conversely, IL6-sufficient colon and pancreatic tumor grow at similar rate in WT and IL6-deficient mice. However, overexpression of IL6 in colon tumor cells significantly increases tumor growth in vivo. Our findings determine that a high tumor local IL6 threshold is essential for IL6 function in colon tumor promotion and targeting the IL6-expressing PMN-MDSCs is potentially an effective approach to suppress colon tumor growth in vivo.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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ez JP Abstract Kidney cancer accounts for 2.5% of all cancers, with an annual global incidence of almost 300,000 cases leading to 111,000 deaths. Approximately 85% of kidney tumors are renal cell carcinoma (RCC) and their major histologic subtype is clear cell renal cell carcinoma (ccRCC). Although new therapeutic treatments are being designed and applied based on the combination of tyrosine kinase inhibitors and immunotherapy, no major impact on the mortality has been reported so far. MRP4 is a pump efflux that transporters multiple endogenous and exogenous substances. Recently it has been associated with tumoral...
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Tags: Int J Biol Macromol Source Type: research
AbstractCleavage of the MUC1 glycoprotein yields two subunits, an extracellular alpha-subunit bound to a smaller transmembrane beta-subunit. Monoclonal antibodies (mAbs) directed against the MUC1 alpha –beta junction comprising the SEA domain, a stable cell-surface moiety, were generated. Sequencing of all seven anti-SEA domain mAbs showed that they clustered into four groups and sequences of all groups are presented here. mAb DMB5F3 with picomolar affinity for the MUC1 SEA target was selected f or further evaluation. Immunohistochemical staining of a series of malignancies with DMB5F3 including lung, prostate, breas...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
CONCLUSION: RT-PCR was found to be more sensitive in detecting PD-L1 expression than conventional IHC. This study may provide an important starting point and useful background information for future research about immunotherapy for appendix, stomach and small intestine neuroendocrine carcinomas. PMID: 31128036 [PubMed - in process]
Source: Journal of B.U.ON. - Category: Cancer & Oncology Tags: J BUON Source Type: research
Discussion MDSCs violently emerge in pathological conditions in an attempt to limit potentially harmful immune and inflammatory responses. Mechanisms supporting their expansion and survival are deeply investigated in cancer, in the perspective to reactivate specific antitumor responses and prevent their contribution to disease evolution. These findings will likely contribute to improve the targeting of MDSCs in anticancer immunotherapies, either alone or in combination with immune checkpoint inhibitors. New evidence indicates that the expansion of myeloid cell differentiation in pathology is subject to fine-tuning, as its...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Alessandro Poggi1*, Roberto Benelli2, Roberta Venè1, Delfina Costa1, Nicoletta Ferrari1, Francesca Tosetti1 and Maria Raffaella Zocchi3 1Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy 2Immunology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy 3Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy It is well established that natural killer (NK) cells are involved in both innate and adaptive immunity. Indeed, they can recognize molecules induced at the cell surface by stress signals ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Michal Yalon1†, Amos Toren1,2†, Dina Jabarin2, Edna Fadida3, Shlomi Constantini3 and Ruty Mehrian-Shai1* 1Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel 2The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel 3Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv-Sourasky Medical Center, Tel Aviv, Israel Pediatric brain tumors are the most common solid tumor type and the leading cause of cancer-related death in children. The immune system plays an important r...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In this study, we evaluated the therapeutic benefit of combining the TAB004 antibody with Liposomal-MSA-IL-2 in immune competent and human MUC1 transgenic (MUC1.Tg) mouse models of PDA and investigated the associated immune responses. Treatment with TAB004 + Lip-MSA-IL-2 resulted in significantly improved survival and slower tumor growth compared to controls in MUC1.Tg mice bearing an orthotopic PDA.MUC1 tumor. Similarly, in the spontaneous model of PDA that expresses human MUC1, the combination treatment stalled the progression of pancreatic intraepithelial pre-neoplastic (PanIN) lesion to adenocarcinoma. Treatment with t...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions Several model systems are now available to characterize the MSC-tumour interplay in the TME. These offer early promise in establishing robust preclinical platforms for the identification of crucial molecular pathways and for the assessment of clinical efficacy of novel drugs to inhibit cancer development and progression. However, selection of the right model for a given study should be shaped on the purpose, and should also consider fixed biological, biochemical, and biophysical parameters according to the specific tumour type. Finally, in order to get reliable and useful results to be translated to the clinic...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions This review describes how leukocyte-heparanase can be a double-edged sword in tumor progression; it can enhance tumor immune surveillance and tumor cell clearance, but also promote tumor survival and growth. We also discuss the potential of using heparanase in leukocyte therapies against tumors, and the effects of heparanase inhibitors on tumor progression and immunity. We are just beginning to understand the influence of heparanase on a pro/anti-tumor immune response, and there are still many questions to answer. How do the pro/anti-tumorigenic effects of heparanase differ across different cancer types? Does...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions and Future Perspectives It is now evident that NK/ILC family plays a pivotal role in the immune defenses. Recent studies in murine and human settings demonstrated that the expression of several inhibitory checkpoints, that may be detrimental in the tumor context, is not restricted to T lymphocytes, revealing an important, yet poorly appreciated, contribution of their expression on innate immune cells. Thus, in the recent years different immunotherapy approaches, based on the blockade of inhibitory NK cell receptors, have been developed in order to unleash NK cell cytotoxicity. This is particularly important in...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
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