共查询到20条相似文献,搜索用时 31 毫秒
1.
Pratima Sinha Suzanne Ostrand-Rosenberg 《Cancer immunology, immunotherapy : CII》2013,62(11):1663-1673
Myeloid cells play a crucial role in tumor progression. The most common tumor-infiltrating myeloid cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAMs). These cells promote tumor growth by their inherent immune suppressive activity which is enhanced by their cross-talk. The root extract of the plant Withania somnifera (Ashwagandha) (WRE) has been reported to reduce tumor growth. HPLC analysis identified Withaferin A (WA) as the most abundant constituent of WRE and led us to determine whether the anti-tumor effects of WRE and WA involve modulating MDSC and TAM activity. A prominent effect of MDSC is their production of IL-10 which increases upon cross-talk with macrophages, thus polarizing immunity to a pro-tumor type 2 phenotype. In vitro treatment with WA decreased MDSC production of IL-10 and prevented additional MDSC production of IL-10 generated by MDSC–macrophage cross-talk. Macrophage secretion of IL-6 and TNFα, cytokines that increase MDSC accumulation and function, was also reduced by in vitro treatment with WA. Much of the T-cell suppressive activity of MDSC is due to MDSC production of reactive oxygen species (ROS), and WA significantly reduced MDSC production of ROS through a STAT3-dependent mechanism. In vivo treatment of tumor-bearing mice with WA decreased tumor weight, reduced the quantity of granulocytic MDSC, and reduced the ability of MDSC to suppress antigen-driven activation of CD4+ and CD8+ T cells. Thus, adjunctive treatment with WA reduced myeloid cell-mediated immune suppression, polarized immunity toward a tumor-rejecting type 1 phenotype, and may facilitate the development of anti-tumor immunity. 相似文献
2.
3.
Alejandro J. Garcia Marcus Ruscetti Teresita L. Arenzana Linh M. Tran Daniella Bianci-Frias Elysia Sybert Saul J. Priceman Lily Wu Peter S. Nelson Stephen T. Smale Hong Wu 《Molecular and cellular biology》2014,34(11):2017-2028
Chronic inflammation is known to be associated with prostate cancer development, but how epithelium-associated cancer-initiating events cross talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs) occurring intraprostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1+ CD11b+ cells, but not those isolated from the spleen of the same tumor-bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, the loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf1 and Il1b, two genes known to induce MDSC expansion and immunosuppressive activities. Treatment of Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epithelium-associated tumor-initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression. 相似文献
4.
Accumulating evidence suggests that the success of some anticancer therapies not only relies on their direct cytotoxicity on tumor cells but also on their ability to promote anticancer immune responses. However, immunosuppressive cells such as Myeloid Derived Suppressor Cells (MDSC) that are generated during tumor progression blunt antitumor immune responses and thus represent a major obstacle to the clinical implementation of immunotherapy protocols. We have recently identified 5-Fluorouracil (5-FU) as an anticancer agent that selectively induced MDSC apoptotic cell death in vitro and in vivo. The elimination of MDSC by 5-FU increased IFNγ secretion by tumor specific CD8(+) T cells infiltrating the tumor and promoted T-cell dependent antitumor responses in vivo, suggesting that some anticancer therapies can reverse tumor-mediated immunosuppression. Here, we review the molecular pathways leading to the induction of MDSC in cancer and discuss how different anticancer agents successfully target these cells in vivo, thereby restoring potent anticancer immunity. 相似文献
5.
Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth 总被引:1,自引:0,他引:1
Porembka MR Mitchem JB Belt BA Hsieh CS Lee HM Herndon J Gillanders WE Linehan DC Goedegebuure P 《Cancer immunology, immunotherapy : CII》2012,61(9):1373-1385
Purpose
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA).Experimental design
Peripheral blood, bone marrow, and tumor samples were collected from pancreatic cancer patients, analyzed for MDSC (CD15+CD11b+) by flow cytometry and compared to cancer-free controls. The suppressive capacity of MDSC (CD11b+Gr-1+) and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid, a potent aminobisphosphonate previously shown to target MDSC. The tumor microenvironment was analyzed for MDSC (Gr1+CD11b+), effector T cells, and tumor cytokine levels.Results
Patients with PA demonstrated increased frequency of MDSC in the bone marrow and peripheral circulation which correlated with disease stage. Normal pancreas tissue showed no MDSC infiltrate, while human tumors avidly recruited MDSC. Murine tumors similarly recruited MDSC that suppressed CD8+ T cells in vitro and accelerated tumor growth in vivo. Treatment with zoledronic acid impaired intratumoral MDSC accumulation resulting in delayed tumor growth rate, prolonged median survival, and increased recruitment of T cells to the tumor. This was associated with a more robust type 1 response with increased levels of IFN-γ and decreased levels of IL-10.Conclusions
MDSC are important mediators of tumor-induced immunosuppression in pancreatic cancer. Inhibiting MDSC accumulation with zoledronic acid improves the host anti-tumor response in animal studies suggesting that efforts to block MDSC may represent a novel treatment strategy for pancreatic cancer. 相似文献6.
Mazorra Z Mesa C Fernández A Fernández LE 《Cancer immunology, immunotherapy : CII》2008,57(12):1771-1780
Preventive immunotherapy is an attractive strategy for patients at a high risk of having cancer. The success of prophylactic
cancer vaccines would depend on the selection of target antigens that are essential for tumour growth and progression. The
overexpression of GM3 ganglioside in murine and human melanomas and its important role in tumour progression makes this self
antigen a potential target for preventive immunotherapy of this neoplasm. We have previously shown that preventive administration
of a GM3-based vaccine to C57BL/6 mice elicited the rejection of the GM3 positive-B16 melanoma cells in most of the animals.
Despite the crucial role of cellular immune response in tumour protection, the involvement of T cells in anti-tumour immunity
of ganglioside vaccines is not described. Here, we examined the mechanisms by which this immunogen confers tumour protection.
We have found that induction of anti-GM3 IgG antibodies correlated with tumour protection. Surprisingly, CD8+ T cells, but not NK1.1+ cells, are required in the effector phase of the antitumour immune response. The depletion of CD4+ T cells during immunization phase did not affect the anti-tumour activity. In addition, T cells from surviving-immunized
animals secreted IFNγ when were co-cultured with IFNα-treated B16 melanoma cells or DCs pulsed with melanoma extract. Paradoxically,
in spite of the glycolipidic nature of this antigen, these findings demonstrate the direct involvement of the cellular immune
response in the anti-tumour protection induced by a ganglioside-based vaccine.
Grant support: Center of Molecular Immunology, Elea Laboratories and Recombio. 相似文献
7.
NKG2D ligand RAE1ε induces generation and enhances the inhibitor function of myeloid‐derived suppressor cells in mice
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Li Qian Weijuan Gong Xiaoqin Jia Lu Liu Feng Ye Jingjuan Ding Yuwei Xu Yi Fu Fang Tian 《Journal of cellular and molecular medicine》2017,21(9):2046-2054
Expression of surface NKG2D ligands on tumour cells, which activates nature killer (NK) cells and CD8+ T cells, is crucial in antitumour immunity. Some types of tumours have evolved mechanisms to suppress NKG2D‐mediated immune cell activation, such as tumour‐derived soluble NKG2D ligands or sustained NKG2D ligands produced by tumours down‐regulate the expression of NKG2D on NK cells and CD8+ T cells. Here, we report that surface NKG2D ligand RAE1ε on tumour cells induces CD11b+Gr‐1+ myeloid‐derived suppressor cell (MDSC) via NKG2D in vitro and in vivo. MDSCs induced by RAE1ε display a robust induction of IL‐10 and arginase, and these MDSCs show greater suppressive activity by inhibiting antigen‐non‐specific CD8+ T‐cell proliferation. Consistently, upon adoptive transfer, MDSCs induced by RAE1ε significantly promote CT26 tumour growth in IL‐10‐ and arginase‐dependent manners. RAE1ε moves cytokine balance towards Th2 but not Th1 in vivo. Furthermore, RAE1ε enhances inhibitory function of CT26‐derived MDSCs and promotes IL‐4 rather than IFN‐γ production from CT26‐derived MDSCs through NKG2D in vitro. Our study has demonstrated a novel mechanism for NKG2D ligand+ tumour cells escaping from immunosurveillance by facilitating the proliferation and the inhibitory function of MDSCs. 相似文献
8.
Stephanie K. Bunt Ashley M. Mohr Jennifer M. Bailey Paul M. Grandgenett Michael A. Hollingsworth 《Cancer immunology, immunotherapy : CII》2013,62(2):225-236
Pancreatic ductal adenocarcinoma is a leading cause of cancer mortality with a dismal 2–5 % 5-year survival rate. Monotherapy with Gemcitabine has limited success, highlighting the need for additional therapies that enhance the efficacy of current treatments. We evaluated the combination of Gemcitabine and Rosiglitazone, an FDA-approved drug for the treatment of type II diabetes, in an immunocompetent transplantable mouse model of pancreatic cancer. Tumor progression, survival, and metastases were evaluated in immunocompetent mice with subcutaneous or orthotopic pancreatic tumors treated with Pioglitazone, Rosiglitazone, Gemcitabine, or combinations of these. We characterized the impact of high-dose Rosiglitazone and Gemcitabine therapy on immune suppressive mediators, including MDSC and T regulatory cells, and on modulation of peripheral and intra-tumoral T cell populations. Combinations of Rosiglitazone and Gemcitabine significantly reduced tumor progression and metastases, enhanced apoptosis, and significantly extended overall survival compared to Gemcitabine alone. Rosiglitazone altered tumor-associated immune suppressive mediators by limiting early MDSC accumulation and intra-tumoral T regulatory cells. Combination therapy with Rosiglitazone and Gemcitabine modulated T cell populations by enhancing circulating CD8+ T cells and intra-tumoral CD4+ and CD8+ T cells while limiting T regulatory cells. The results suggest that Rosiglitazone, in combination with Gemcitabine, decreases immune suppressive mechanisms in immunocompetent animals and provides pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic cancer. 相似文献
9.
Bastian H?chst Julita Mikulec Tania Baccega Christina Metzger Meike Welz Julia Peusquens Frank Tacke Percy Knolle Christian Kurts Linda Diehl Isis Ludwig-Portugall 《PloS one》2015,10(3)
CD11b+Gr1+ myeloid derived suppressor cells (MDSC) are known to be very potent suppressors of T cell immunity and can be further stratified into granulocytic MDSC and monocytic MDSC in mice based on expression of Ly6G or Ly6C, respectively. Here, using these markers and functional assays, we aimed to identify whether MDSC are induced during chronic inflammation leading to fibrosis in both kidney and liver and whether additional markers could more specifically identify these MDSC subsets. In an adenine-induced model of kidney inflammation/fibrosis suppressive Ly6Gpos MDSC were induced. The suppressive function within the Ly6G+ MDSC population was exclusively present in IFNγRβ expressing cells. In contrast, in chronic inflammation in the liver induced by bile duct ligation, suppressive capacity was exclusively present in the Ly6Cpos MDSC subset. Gene expression analyses confirmed the differential origins and regulation of those MDSC subsets. Additionally, depletion of MDSC in either kidney or liver fibrosis enhanced fibrosis markers, indicating a protective role for MDSC in organ fibrosis. Thus, our data demonstrate that during liver inflammation and kidney fibrosis MDSC with similar function arise bearing a distinct marker profile and arising from different cell populations. 相似文献
10.
Mohammad-Javad Sanaei Fatemeh Taheri Masoud Heshmati Davood Bashash Roya Nazmabadi Faramarz Mohammad-Alibeigi Mahboobeh Nahid-Samiei Hedayatollah Shirzad Nader Bagheri 《Cell biology international》2021,45(10):2086-2095
Prostate cancer (PCa) is one of the most epidemic types of cancer in men. The tumor microenvironment (TME) of PCa is involved in the emergence of immunosuppressive factors such as myeloid-derived suppressor cells (MDSC), which regulate the immune system by several mechanisms, including interleukin (IL)-10 production. On the other hand, IL-17+ helper T cells (Th17) induce MDSCs and chronic inflammation in TME by producing IL-17. This study demonstrated that the frequency of CD33+ pSTAT3+ MDSC and IL-17+ lymphocyte as well as IL-10 messenger RNA (mRNA) expression were significantly higher in the PCa patients than in the benign prostatic hyperplasia (BPH) group. Moreover, there was no significant relationship between the frequency of CD33+ pSTAT3+ MDSC, and IL-17+ lymphocyte with Gleason scores in the PCa group. We suggested that the higher frequency of CD33+ pSTAT3+ MDSC and IL-17+ lymphocyte and the more frequent expression of IL-10 mRNA in PCa patients may play roles in tumor progression from BPH to PCa. 相似文献
11.
Elham Safarzadeh Shahryar Hashemzadeh Pascal H.G. Duijf Behzad Mansoori Vahid Khaze Ali Mohammadi Tohid Kazemi Mehdi Yousefi Milad Asadi Hamed Mohammadi Farhad Babaie Behzad Baradaran 《Journal of cellular physiology》2019,234(4):3515-3525
Evading immune destruction is a hallmark of cancer. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid immune cells, are thought to foster the establishment of an immunosuppressive tumor microenvironment, but it remains unclear how. This study aims to determine the levels of circulating MDSCs and their subpopulations and test their immunosuppressive functions in patients with breast cancer (BC). We analyzed the fractions of MDSCs in freshly isolated peripheral blood mononuclear cells of patients with BC and healthy donors using flow cytometry. Circulating MDSCs were further phenotyped using fluorescently labeled antihuman monoclonal antibodies. Coculture experiments revealed the effects of MDSCs on CD3+ T cell response. Moreover, we correlated circulating MDSC levels with clinicopathological features of patients with BC. We show that the fraction of HLA-DR – CD33 + MDSCs in peripheral blood is about 10-fold higher in patients with BC than in healthy control individuals. The levels of all MDSC subpopulations, including monocytic and granulocytic MDSCs, are significantly elevated. Coculture experiments of purified HLA-DR – CD33 + MDSCs and CD3 + T cells demonstrate that T cell proliferation is more effectively inhibited by BC patient-derived MDSCs than by healthy control MDSCs. Moreover, increased circulating MDSC levels robustly associate with advanced BC stage and positive lymph node status. By being more abundant and more effective T cell suppressors, BC patient-derived circulating MDSCs exert a dual immunosuppressive effect. Our findings pave the way to develop novel diagnostic and immunotherapeutic strategies, aimed at detecting and inhibiting MDSCs in patients with BC. 相似文献
12.
Chaitanya Kumar Sakshi Kohli Poonamalle Parthasarathy Bapsy Ashok Kumar Vaid Minish Jain Venkata Sathya Suresh Attili Bandana Sharan 《Journal of biosciences》2017,42(1):161-173
The interplay between host immunity and tumour cells has opened the possibility of targeting tumour cells by modulation of the human immune system. Cancer immunotherapy involves the treatment of a tumour by utilizing the recombinant human immune system components to target the pro-tumour microenvironment or by revitalizing the immune system with the ability to kill tumour cells by priming the immune cells with tumour antigens. In this review, current immunotherapy approaches to cancer with special focus on dendritic cell (DC)-based cancer vaccines are discussed. Some of the DC-based vaccines under clinical trials for various cancer types are highlighted. Establishing tumour immunity involves a plethora of immune components and pathways; hence, combining chemotherapy, radiation therapy and various arms of immunotherapy, after analysing the benefits of individual therapeutic agents, might be beneficial to the patient. 相似文献
13.
G-Andre Banat Aleksandra Tretyn Soni Savai Pullamsetti Jochen Wilhelm Andreas Weigert Catherine Olesch Katharina Ebel Thorsten Stiewe Friedrich Grimminger Werner Seeger Ludger Fink Rajkumar Savai 《PloS one》2015,10(9)
Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3+), cytotoxic-T cells (CD8+), T-helper cells (CD4+), B cells (CD20+), macrophages (CD68+), mast cells (CD117+), mononuclear cells (CD11c+), plasma cells, activated-T cells (MUM1+), B cells, myeloid cells (PD1+) and neutrophilic granulocytes (myeloperoxidase+) compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1+ cells) in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition. 相似文献
14.
《Trends in biochemical sciences》2023,48(7):597-609
The metabolic cross-talk between cancer cells and T cells dictates cancer formation and progression. These cells possess metabolic plasticity. Thus, they adapt their metabolic profile to meet their phenotypic requirements. However, the nutrient microenvironment of a tumor is a very hostile niche in which these cells are forced to compete for the available nutrients. The hyperactive metabolism of tumor cells often outcompetes the antitumorigenic CD8+ T cells while promoting the protumorigenic exhausted CD8+ T cells and T regulatory (Treg) cells. Thus, cancer cells elude the immune response and spread in an uncontrolled manner. Identifying the metabolic pathways necessary to shift the balance from a protumorigenic to an antitumorigenic immune phenotype is essential to potentiate antitumor immunity. 相似文献
15.
Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor 总被引:1,自引:0,他引:1
Toh B Wang X Keeble J Sim WJ Khoo K Wong WC Kato M Prevost-Blondel A Thiery JP Abastado JP 《PLoS biology》2011,9(9):e1001162
In order to metastasize, cancer cells need to acquire a motile phenotype. Previously, development of this phenotype was thought to rely on the acquisition of selected, random mutations and thus would occur late in cancer progression. However, recent studies show that cancer cells disseminate early, implying the existence of a different, faster route to the metastatic motile phenotype. Using a spontaneous murine model of melanoma, we show that a subset of bone marrow-derived immune cells (myeloid-derived suppressor cells or MDSC) preferentially infiltrates the primary tumor and actively promotes cancer cell dissemination by inducing epithelial-mesenchymal transition (EMT). CXCL5 is the main chemokine attracting MDSC to the primary tumor. In vitro assay using purified MDSC showed that TGF-β, EGF, and HGF signaling pathways are all used by MDSC to induce EMT in cancer cells. These findings explain how cancer cells acquire a motile phenotype so early and provide a mechanistic explanation for the long recognized link between inflammation and cancer progression. 相似文献
16.
The immune system has evolved mechanisms to protect the host from the deleterious effects of inflammation. The generation of immune suppressive cells like myeloid derived suppressor cells (MDSCs) that can counteract T cell responses represents one such strategy. There is an accumulation of immature myeloid cells or MDSCs in bone marrow (BM) and lymphoid organs under pathological conditions such as cancer. MDSCs represent a population of heterogeneous myeloid cells comprising of macrophages, granulocytes and dendritic cells that are at early stages of development. Although, the precise signaling pathways and molecular mechanisms that lead to MDSC generation and expansion in cancer remains to be elucidated. It is widely believed that perturbation of signaling pathways involved during normal hematopoietic and myeloid development under pathological conditions such as tumorogenesis contributes to the development of suppressive myeloid cells. In this review we discuss the role played by key signaling pathways such as PI3K, Ras, Jak/Stat and TGFb during myeloid development and how their deregulation under pathological conditions can lead to the generation of suppressive myeloid cells or MDSCs. Targeting these pathways should help in elucidating mechanisms that lead to the expansion of MDSCs in cancer and point to methods for eliminating these cells from the tumor microenvironment. 相似文献
17.
Malignant melanoma is known by its rapid progression and poor response to currently applied treatments. Despite the well-documented
melanoma immunogenicity, the results of immunotherapeutic clinical trials are not satisfactory. This poor antitumor reactivity
is due to the development of chronic inflammation in the tumor microenvironment characterized by infiltrating leukocytes and
soluble mediators, which lead to an immunosuppression associated with cancer progression. Using the ret transgenic mouse melanoma model that closely resembles human melanoma, we demonstrated increased levels of chronic inflammatory
factors in skin tumors and metastatic lymph nodes, which correlated with tumor progression. Furthermore, Gr1+CD11b+ myeloid-derived suppressor cells (MDSC), known to block tumor-reactive T cells, were enriched in melanoma lesions and showed
an enhanced immunosuppressive capacity. This MDSC accumulation was associated with a strong TCR ζ-chain downregulation in
T cells suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity.
Indeed, upon administration of phosphodiesterase-5 inhibitor sildenafil or paclitaxel in non-cytotoxic doses, we observed
reduced levels of chronic inflammatory mediators in association with decreased MDSC amounts and immunosuppressive function.
This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing
mice. CD8 T-cell depletion resulted in an abrogation of beneficial outcome of both drugs, suggesting the involvement of MDSC
and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment
should be applied in conjunction with melanoma immunotherapies to increase their efficacy. 相似文献
18.
Heidi E. Godoy A. Nazmul H. Khan R. Robert Vethanayagam Melissa J. Grimm Kelly L. Singel Nonna Kolomeyevskaya Kevin J. Sexton Anupama Parameswaran Scott I. Abrams Kunle Odunsi Brahm H. Segal 《PloS one》2013,8(7)
The phagocyte NADPH oxidase generates superoxide anion and downstream reactive oxidant intermediates in response to infectious threat, and is a critical mediator of antimicrobial host defense and inflammatory responses. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are recruited by cancer cells, accumulate locally and systemically in advanced cancer, and can abrogate anti-tumor immunity. Prior studies have implicated the phagocyte NADPH oxidase as being an important component promoting MDSC accumulation and immunosuppression in cancer. We therefore used engineered NADPH oxidase-deficient (p47phox−/−) mice to delineate the role of this enzyme complex in MDSC accumulation and function in a syngeneic mouse model of epithelial ovarian cancer. We found that the presence of NADPH oxidase did not affect tumor progression. The accumulation of MDSCs locally and systemically was similar in tumor-bearing wild-type (WT) and p47phox−/− mice. Although MDSCs from tumor-bearing WT mice had functional NADPH oxidase, the suppressive effect of MDSCs on ex vivo stimulated T cell proliferation was NADPH oxidase-independent. In contrast to other tumor-bearing mouse models, our results show that MDSC accumulation and immunosuppression in syngeneic epithelial ovarian cancer is NADPH oxidase-independent. We speculate that factors inherent to the tumor, tumor microenvironment, or both determine the specific requirement for NADPH oxidase in MDSC accumulation and function. 相似文献
19.
Qiangda Chen Ning Pu Hanlin Yin Jicheng Zhang Guochao Zhao Wenhui Lou Wenchuan Wu 《Journal of cellular and molecular medicine》2020,24(15):8674-8686
CD73 is a glycosylphosphatidylinositol (GPI)‐anchored protein that attenuates tumour immunity via cooperating with CD39 to generate immunosuppressive adenosine. Therefore, CD73 blockade has been incorporated into clinical trials for cancers based on preclinical efficacy. However, the biological role and underlying mechanism of CD73 in pancreatic cancer (PC) microenvironment and its prognostic impact have not been comprehensively studied. In this article, we found that the expression of CD73 was up‐regulated in PC tissues and patients with higher CD73 expression had poorer overall survival (OS) and disease‐free survival (DFS) in multiple publicly available databases. Higher CD73 expression was significantly associated with its reduced methylation, and only the hypomethylation of CpG site at cg23172664 was obviously correlated with poorer OS. Then, Metascape analysis and GSEA showed that CD73 may play an important role in PC progression and immune regulations. Notably, CD73 was verified to be negatively correlated with infiltrating levels of CD8+ T cells and γδ+ T cells in both TCGA and GEO cohorts via the CIBERSORT algorithm. In addition, patients with higher CD73 expression also tended to have higher PD‐L1 expression and tumour mutation load. It seemed that CD73 might be a promising biomarker for the response to the anti‐PD‐1/PD‐L1 treatment in PC. In conclusion, these results reveal that CD73 may function as a promotor in cancer progression and a regulator in immune patterns via CD73‐related pathways. Blockade of CD73 might be a promising therapeutic strategy for PC. 相似文献
20.
Alessandra Battaglia Alexia Buzzonetti Cinzia Baranello Gabriella Ferrandina Enrica Martinelli Francesco Fanfani Giovanni Scambia Andrea Fattorossi 《Cancer immunology, immunotherapy : CII》2009,58(9):1363-1373
Objective We compared the immune system state in metastatic tumour draining lymph nodes (mTDLN) and metastasis free TDLN (mfTDLN) in
53 early stage cervical cancer patients to assess whether the presence of metastatic tumour cells worsen the balance between
an efficacious anti-tumour and a tolerogenic microenvironment.
Methods The immune system state was measured by immunophenotypic and functional assessment of suppressor and effector immune cell
subsets.
Results Compared to mfTDLN, mTDLN were significantly enriched in CD4+Foxp3+ regulatory T cells (Treg), which, in addition, exhibited an activated phenotype (HLA-DR+ and CD69+). Treg in mTDLN were also significantly enriched in neuropilin-1 (Nrp1) expressing cells, a subset particularly potent in
dampening T cell responses. mTDLN tended to be enriched in a population of CD8+Foxp3+T cells (operationally defined as CD8+Treg) that showed a suppressor potency similar to Treg under the same experimental conditions. Plasmacytoid dendritic cells
(pDC) and myeloid DC (mDC) generally show distinct roles in inducing T cell tolerance and activation, respectively. In line
with the excess of suppressor T cells, the ratio pDC to mDC was significantly increased in mTDLN. Immunohistochemical testing
showed that metastatic tumour cells produced the vascular endothelial growth factor, a natural ligand for Nrp1 expressed on
the cell surface of Nrp1+Treg and pDC, and therefore a potential mediator by which tumour cells foster immune privilege in mTDLN. Consistent with the
overall tolerogenic profile, mTDLN showed a significant Tc2 polarisation and tended to contain lower numbers of CD45RA+CD27− effector memory CD8+T cells.
Conclusions The increased recruitment of suppressor type cells concomitant with the scarcity of cytotoxic type cells suggests that in
mTDLN the presence of tumour cells could tip the balance against anti-tumour immune response facilitating the survival of
metastatic tumour cells and possibly contributing to systemic tolerance. 相似文献