T-Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis

Facciabene, Andrea; Motz, Gregory T.; Coukos, George

doi:10.1158/0008-5472.can-11-3687

Cited by 693 publications

(600 citation statements)

References 107 publications

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“…In the tumor microenvironment, tumor-infiltrating immunosuppressive cells, including Treg cells, MDSCs, alternatively activated macrophages (M2), and immature/tolerogenic DC, inhibit anticancer immunity and play a role in tumor angiogenesis and cancer cell survival, proliferation, and metastatic potential. 50,51 In the present study, we delineated a role for NPC T-MDSCs in directly promoting NPC cell migration, invasion and metastasis. First, we found that T-MDSCs increase cancer migration and invasion via the induction of EMT in NPC cells in vitro.…”

Section: Discussionmentioning

confidence: 92%

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

OuYang

et al. 2015

OncoImmunology

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Keywords: COX-2, myeloid-derived suppressor cells, nasopharyngeal carcinomaAbbreviations: ARG-1, arginase 1; COX-2, cyclooxygenase-2; DFS, disease-free survival; EMT, epithelial-mesenchymal transition; GM-CSF, granulocyte-monocyte-colony stimulating factor; iNOS, inducible nitric oxide synthase; LNMMA, L-NG-monomethylarginine; MDSCs, myeloid-derived suppressor cells; NAC, N-acetylcysteine; NOHA, N-hydroxy-nor-L-arginine; NOX2, NADPH oxidase; NPC, nasopharyngeal carcinoma; ROS, reactive oxygen species; siRNA, small interfering RNA; TCF4, T-cell factor 4; TGF, transforming growth factor b; T-MDSCs, tumor-induced MDSCs; VEGF, vascular endothelial growth factorThe expansion of myeloid-derived suppressor cells (MDSCs) is a common feature of cancer, but its biological roles and molecular mechanism remain unclear. Here, we investigated a molecular link between MDSC expansion and tumor cell metastasis in nasopharyngeal carcinoma (NPC). We demonstrated that MDSCs expanded and were positively correlated with the elevated tumor COX-2 expression and serum IL-6 levels in NPC patients. Importantly, COX-2 and MDSCs were poor predictors of patient disease-free survival (DFS). Knocking down tumor COX-2 expression hampered functional TW03-mediated-MDSC cell (T-MDSC) induction with IL-6 blocking. We identified that T-MDSCs promoted NPC cell migration and invasion by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact, and TMDSCs enhanced tumor experimental lung metastasis in vivo. Interestingly, the contact between T-MDSCs and NPC cells enhanced tumor COX-2 expression, which subsequently activated the b-catenin/TCF4 pathway, resulting in EMT of the cancer cells. Blocking transforming growth factor b (TGFb) or inducible nitric oxide synthase (iNOS) significantly abolished the T-MDSC-induced upregulation of COX-2 and EMT scores in NPC cells, whereas the administration of TGFb or L-arginine supplements upregulated COX-2 expression and EMT scores in NPC cells. These findings reveal that COX-2 is a key factor mediating the interaction between MDSCs and tumor cells, suggesting that the inhibition of COX-2 or MDSCs has the potential to suppress NPC metastasis.

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Section: Discussionmentioning

confidence: 92%

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

OuYang

et al. 2015

OncoImmunology

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“…The finding that this proliferation is much greater in mice with impaired Treg function suggests that the proliferation behaves similar to an immune system-sensitive carcinoma. The finding that depletion of Tregs allows progressive epithelial growth raises questions about the recent depletion of Tregs to enhance the immune response in cancer therapy (14).…”

Section: Epithelial Proliferationmentioning

confidence: 99%

Intraepithelial T-Cell Cytotoxicity, Induced Bronchus-Associated Lymphoid Tissue, and Proliferation of Pneumocytes in Experimental Mouse Models of Influenza

Sell

Guest²,

McKinstry³

et al. 2014

Viral Immunology

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Immunopathologic examination of the lungs of mice with experimental influenza virus infection reveals three prominent findings. (i) There is rapidly developing perivasuclar (arterial) and peribronchial infiltration with Tcells and invasion of T-cells into the bronchiolar epithelium, separation of epithelial cells from each other and from the basement membrane, leading to defoliation of the bronchial epithelium. This reaction is analogous to a viral exanthema of the skin, such as measles and smallpox. This previously described but unappreciated reaction most likely is an effective way to eliminate virus-infected cells, but may contribute to acute toxicity and mortality.(ii) After this, there is formation of dense collections of lymphocytes adjacent to bronchi consisting mainly of Bcells, with a scattering of T-cells and macrophages. This is known as induced bronchial-associated lymphoid tissue (iBALT) and correlates with increased interleukin (IL)-17 in the lung. iBALT provides sites for a local immune reaction in the lung to both the original infection and related viral infections (heterologous immunity). (iii) Within the first 2-3 weeks, there is proliferation of type II pneumocytes and/or terminal bronchial epithelial cells extending from the terminal bronchioles into the adjacent alveoli, eventually leading to large zones of the lung filled with tumor-like epithelial cells with squamous metaplasia. The proliferation correlates with IL-17 and IL-22 expression, and the extent of this reaction appears to be determined by the availability of T-regulatory cells.

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“…This immune environment works to either suppress or promote cancer cell growth through various mechanisms. [7][8][9][10] For example, TILs are often observed in many types of solid tumors; in some cases they are considered to reflect the host immune system that responds to and eliminates the tumor cells. In fact, higher TIL infiltration has been reported to correlate with better prognosis in many tumor types, [11][12][13][14][15] including ovarian cancer for which a high degree of intratumoral CD8 C T cell was correlated with better clinical response to platinum agents.…”

Section: Introductionmentioning

confidence: 99%

Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing

et al. 2015

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Tumor-infiltrating lymphocytes (TILs) play an important role in regulating the host immune response and are one of key factors in defining tumor microenvironment. Some studies have indicated that T cell infiltration in malignant ascites is associated with clinical outcome, but few studies have performed detailed characterization of T cell diversity or clonality in malignant effusions. We have applied a next generation sequencing method to characterize T cell repertoire of a set of primary cancers, ascites, and blood from 12 ovarian cancer patients and also analyzed the T cell subtype populations in malignant fluids from 3 ovarian cancer patients. We observed enrichment of certain T cells in tumors and ascites, but most of the enriched T cell receptor (TCR) sequences in tumors and ascites were not common. Moreover, we analyzed TCR sequences of T cell subtypes (CD4 C , CD8 C , and regulatory T cells) isolated from malignant effusions and also found clonal expansion of certain T cell populations, but the TCR sequences were almost mutually exclusive among the three subgroups. Although functional studies of clonally expanded T cell populations are definitely required, our approach offers a detailed characterization of T cell immune microenvironment in tumors and ascites that might differently affect antitumor immune response.

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T-Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis

Cited by 693 publications

References 107 publications

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

Intraepithelial T-Cell Cytotoxicity, Induced Bronchus-Associated Lymphoid Tissue, and Proliferation of Pneumocytes in Experimental Mouse Models of Influenza

Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing

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