Jian Ye

University of Rochester Medical Center

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Guangyong Peng

Saint Louis University

Eddy C. Hsueh

Saint Louis University

Daniel F. Hoft

Saint Louis University

Chunling Ma

Hebei Medical University

Mark A. Varvares

Massachusetts Eye and Ear Infirmary

Yanping Zhang

Anhui Agricultural University

Yanping Zhang

Hebei Medical University

Pamela Hunborg

Saint Louis University

Wei Mo

Xiamen University

Brian A. Belt

University of Rochester Medical Center

Cooperative Institutions

Saint Louis University

University of Rochester Medical Center

University of Rochester

Nanjing Medical University

Washington University in St. Louis

Saint Louis University

UCLouvain Saint-Louis Brussels

Shandong First Medical University

Yale University

Hangzhou First People's Hospital

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Tumor-Infiltrating γδ T Lymphocytes Predict Clinical Outcome in Human Breast Cancer

The Journal of Immunology (2012)

Chunling Ma Qunyuan Zhang Jian Ye Fang Wang Yanping Zhang

Abstract Understanding and dissecting the role of different subsets of regulatory tumor-infiltrating lymphocytes (TILs) in the immunopathogenesis of individual cancer is a challenge for anti-tumor immunotherapy. High levels of γδ regulatory T cells have been discovered in breast TILs. However, the clinical relevance of these intratumoral γδ T cells is unknown. In this study, γδ T cell populations were analyzed by performing immunohistochemical staining in primary breast cancer tissues from patients with different stages of cancer progression. Retrospective multivariate analyses of the correlations between γδ T cell levels and other prognostic factors and clinical outcomes were completed. We found that γδ T cell infiltration and accumulation in breast tumor sites was a general feature in breast cancer patients. Intratumoral γδ T cell numbers were positively correlated with advanced tumor stages, HER2 expression status, and high lymph node metastasis but inversely correlated with relapse-free survival and overall survival of breast cancer patients. Multivariate and univariate analyses of tumor-infiltrating γδ T cells and other prognostic factors further suggested that intratumoral γδ T cells represented the most significant independent prognostic factor for assessing severity of breast cancer compared with the other known factors. Intratumoral γδ T cells were positively correlated with FOXP3+ cells and CD4+ T cells but negatively correlated with CD8+ T cells in breast cancer tissues. These findings suggest that intratumoral γδ T cells may serve as a valuable and independent prognostic biomarker, as well as a potential therapeutic target for human breast cancer.

Tumor-infiltrating lymphocytes

10.4049/jimmunol.1201892

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Citations (198)

Abstract 781: Plasticity of human tumor-infiltrating Th17 cells

Cancer Research (2011)

Jian Ye Xinming Su Eddy C. Hsueh Yanping Zhang Joyce M. Koenig

Abstract Although Th17 cells play critical roles in the pathogenesis of many inflammatory and autoimmune diseases, their function in human tumor immunity remains largely unknown. We have recently identified Th17 cells as an important component of human tumor-infiltrating lymphocytes (TILs) obtained from melanoma, breast, colon and ovarian cancer patients, but their stability and plasticity in the tumor microenvironment is still unclear. In this study, we generated Th17 clones from TILs. We showed that Th17 clones can differentiate into IFN-gamma-producing and FoxP3+ cells after in vitro stimulation with OKT3 and allogeneic peripheral blood mononuclear cells (PBMCs). We further demonstrated that T cell receptor (TCR) engagement was responsible for this conversion, and that this differentiation was due to the epigenetic modification and reprogramming of gene expression profiles, including lineage-specific transcriptional factor and cytokine genes. In addition to expressing IFN-gamma and FoxP3, we showed that these differentiated Th17 clones mediated potent suppressive function after repetitive stimulation with OKT3, suggesting that these Th17 clones had differentiated into functional Treg cells. We further demonstrated that the Th17-derived Treg cells, unlike naturally occurring CD4+CD25+ Treg cells, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human Th17 cells can differentiate into Treg cells and indicate the substantial developmental plasticity of Th17 cells, which may have clinical implications for the development of novel cancer immunotherapeutic approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 781. doi:10.1158/1538-7445.AM2011-781

Reprogramming

10.1158/1538-7445.am2011-781

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Astragalus membranaceus promotes the function of regulatory t cells from asthma patients in remission periods in vitro

05.01 - Airway pharmacology and treatment (2019)

Hualiang Jin Limin Wang Jian Ye Shenglin Ma

Emerging data demonstrates that the chronic airway inflammation in asthma remission periods is partly attributed to the decreased function of T regulatory (Treg) cells. Astragalus membranaceus (AM), a Traditional Chinese Medicine for treatment of asthma, is confirmed to have a variety of immunomodulatory properties. This study was to explore whether AM possesses potential regulatory effect on the function of Treg cells from the patients with asthma at the remission stage. We enrolled 10 asthma patients in the remission stage and 10 healthy controls. The medicinal serum of AM was prepared from rats. CD4+CD25+ Treg cells and CD4+CD25- conventional T (Tconv) cells in peripheral blood mononuclear cells were sorted by fluorescence activated cell sorting. Treg cells were treated with three doses of AM medicinal serum. The effect of AM on Treg cells proliferation was evaluated by CCK-8 assay. Production of TGF-β, IL-10 and IL-35 cytokines was evaluated in the culture supernatant of Treg cells in the presence of medicinal serum. Suppressor activity of Tregs was examined by changes in the proliferation of CFSE-labeled Tconv cells. AM could significantly increase the proliferation of Treg cells and promote the production of TGF-β, IL-10 and IL-35 cytokines. In functional assay, the immune suppression of Tregs from asthma patients was remarkably decreased compared to that from healthy controls. However, AM increased the immune suppression of Tregs on Tconv cells. In conclusion, this study revealed AM could enhance effects on Treg proliferation and function, which may have potential benefits for asthma treatment in remission periods.

Regulatory T cell

Astragalus

10.1183/13993003.congress-2019.pa4203

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Tumor microenvironments direct the recruitment and expansion of human Th17 cells (100.28)

The Journal of Immunology (2010)

Guangyong Peng Xinming Su Jian Ye Eddy C. Hsueh Yanping Zhang

Abstract Although Th17 cells play critical roles in the pathogenesis of many inflammatory and autoimmune diseases, their prevalence among tumor-infiltrating lymphocytes (TILs) and function in human tumor immunity remains largely unknown. We have recently demonstrated high percentages of Th17 cells in TILs from ovarian cancer patients, but the mechanisms of accumulation of these Th17 cells in the tumor microenvironment are still unclear. In this study, we further showed elevated Th17 cell populations in the TILs obtained from melanoma, breast and colon cancers, suggesting that development of tumor-infiltrating CD4+ Th17 cells may be a general feature in cancer patients. We then demonstrated that tumor microenvironmental RANTES and MCP-1 secreted by tumor cells and tumor-derived fibroblasts mediate the recruitment of Th17 cells. In addition, we found that tumor cells and tumor-derived fibroblasts produce a proinflammatory cytokine milieu as well as provide cell-to-cell contact engagement that facilitates the generation and expansion of Th17 cells. We also showed that inflammatory TLR and NOD2 signaling promote the attraction and generation of Th17 cells induced by tumor cells and tumor-derived fibroblasts. These results identify Th17 cells as an important component of human TILs, demonstrate mechanisms involved in the recruitment and regulation of Th17 cells in tumor microenvironments, and provide new insights relevant for the development of novel cancer immunotherapeutic approaches.

Tumor-infiltrating lymphocytes

Proinflammatory cytokine

10.4049/jimmunol.184.supp.100.28

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Data from Specific Recruitment of γδ Regulatory T Cells in Human Breast Cancer

Jian Ye Chunling Ma Fang Wang Eddy C. Hsueh Károly Tóth

<div>Abstract<p>Understanding the role of different subtypes of tumor-infiltrating lymphocytes (TIL) in the immunosuppressive tumor microenvironment is essential for improving cancer treatment. Enriched γδ1 T-cell populations in TILs suppress T-cell responses and dendritic cell maturation in breast cancer, where their presence is correlated negatively with clinical outcomes. However, mechanism(s) that explain the increase in this class of regulatory T cells (γδ Treg) in patients with breast cancer have yet to be elucidated. In this study, we show that IP-10 secreted by breast cancer cells attracted γδ Tregs. Using neutralizing antibodies against chemokines secreted by breast cancer cells, we found that IP-10 was the only functional chemokine that causes γδ Tregs to migrate toward breast cancer cells. In a humanized NOD-scid IL-2Rγ<sup>null</sup> (NSG) mouse model, human breast cancer cells attracted γδ Tregs as revealed by a live cell imaging system. IP-10 neutralization <i>in vivo</i> inhibited migration and trafficking of γδ Tregs into breast tumor sites, enhancing tumor immunity mediated by tumor-specific T cells. Together, our studies show how γδ Tregs accumulate in breast tumors, providing a rationale for their immunologic targeting to relieve immunosuppression in the tumor microenvironment. <i>Cancer Res; 73(20); 6137–48. ©2013 AACR</i>.</p></div>

Tumor-infiltrating lymphocytes

Immunosuppression

10.1158/0008-5472.c.6504614

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To Investigate Immune Changes in Experimental Colorectal Cancer

Suzhou Daxue xuebao. Faxue ban (2011)

Jian Ye

Objective To explore the changes in immune function in experimental colorectal cancer. Methods Colorectal cancer was induced consistently in experimental S-D rats by the carcinogen 1,2- dimethylhydrazine(DMH).Respectively 16 weeks,21 weeks after the tumorgenensis,the peripheral blood cells and 21 weeks after the tumorgenensis the spleen cells were all detected for the expressions of CD3,CD4,CD8,CD25,4 - 1BB and 4 - 1BBL,and the secretion of IFN-7 in supernatant by spleen cells stimulated by PHA were detected by ELISA.Results The tumorgenensis rate was 100%in all five rats.There were down regulations of CD3~+ and CD3~+ CD4~+ in peripheral blood in the induced group compared with that in the control groups,but there was no significant difference(P0.05);however,21 weeks later,there were significant downregulations of CD3~+ and CD3~+ CD4~+ in peripheral blood and spleen comparing with those in the control groups(P0.05).IFN-γreleased by PHA-stimulated splenocytes decreased significantly by the DMH induced as compared with the controls(P0.01).Conclusion They are close models of human colorectal cancer with similar immune function decline,which mainly show the decline of cellular immune function.

Splenocyte

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An update on IgBLAST, a tool for Ig and TCR sequence analysis

The Journal of Immunology (2016)

Jian Ye

Abstract The variable domain of B and T cell receptor is encoded by multiple genes, including the variable (V) gene, the diversity (D) gene and the joining (J) gene. Previously we developed an analysis tool, IgBLAST, for immunoglobulin sequences (http://www.ncbi.nlm.nih.gov/igblast/). Here we describe our recent update on this tool. The new functionalities include capability to analyze T cell receptor sequences (TR), annotating the CDR3 region, extending alignment to 5′ end of the V region, more flexibility in search criteria and providing summarized information to aid large-scale sequence analysis. We use examples to demonstrate these new functionalities and their implications in Ig and TCR sequence analysis.

Sequence (biology)

Immunoglobulin domain

10.4049/jimmunol.196.supp.138.3

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Downregulation of Nogo-A expression of oligodendrocytes in vitro with antisense oligodeoxynucleotides.

PubMed (2003)

Xijia Peng Shaozhang Liu Jian Ye Rongdi Yuan

To investigate the effect of antisense oligonucleotides (ODN) to Nogo-A mRNA expression in oligodendrocytes and to establish the base for further research of repair of optic nerve injury.(1) Oligodendrocytes were obtained by inoculating the optic nerve of newborn (2 days) rats and were identified with galactocerebroside(GC) antibody immunocytochemical stain. (2) In order to observe the effects of antisense ODN on cultured cells, we set up five groups, including the groups of three concentration of antisense Nogo-A ODN (2 microM, 5 microM, 10 microM), a group with the random sequence added to the medium and the control group. Reverse transcription-polymerase chain reaction (RT-PCR) was adopted to study the effects of ODN on the expression of Nogo-A in oligodendrocytes.(1) Three days after inoculation, a few of round or fusiform shape cells migrated from optic nerve tissue; About 11 days later, the coverlips were completely covered by the cells; The cells identified with GC antibody immunocytochemical stain were positive cells. (2) The result of RT-PCR study showed that antisense Nogo-A ODN could significantly and specifically inhibit the expression of Nogo-A after 24 hours (P < 0.01). Random sequence has no effect on Nogo-A expression.Antisense Nogo-A ODN can effectively and specifically inhibit the expression of Nogo-A.

Galactocerebroside

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Muscone Inhibits the Excessive Inflammatory Response in Myocardial Infarction by Targeting TREM-1

Evidence-based Complementary and Alternative Medicine (2022)

Hong Zhang Jian Ye Xu Wang Zongjun Liu Tao Chen

The inhibitory effect of muscone on the hyperinflammatory response after myocardial ischemia reperfusion injury (MIRI) was investigated, and the target and signal pathways of muscone were explored. The levels of inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor alpha were detected through qRT-PCR and ELISA. The expression levels of p38 and NF-κB signaling pathway-related proteins were detected through Western blot. TREM-1 siRNA was transfected into macrophages in vitro. The rat model of myocardial ischemia was established and used in studying the inhibitory effect of muscone on the inflammatory response and its protective effect muscone on myocardial apoptosis. The expression of TREM-1 was upregulated during myocardial ischemia. Knocking down TREM-1 decreased the increase in inflammatory cytokines in the supernatant of macrophages induced by rmHMGB1 (1 μg/mL) and rmHSP60 (1 mol/mL). In addition, knocking down TREM-1 decreased p38 and NF-κB signaling activation. Muscone can protect myocardial cells by inhibiting the expression of TREM-1 and the inflammatory response after myocardial infarction. Further study showed that muscone inhibited the production of DAM-triggered (damage-associated molecular pattern trigger) inflammatory cytokines. In addition, muscone inhibited the activation of p38 and NF-κB signals under DAM-induced conditions. Muscone and TREM-1 gene knockout reduced cell apoptosis and provided protection against MIRI by inhibiting p38 and NF-κB signaling activation. Mechanism studies showed that muscone inhibited the production and release of inflammatory cytokines by inhibiting TREM-1, and thereby reducing the inflammatory response and providing protection against MIRI.

Proinflammatory cytokine

10.1155/2022/9112479

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TLR7 Signaling Regulates Th17 Cells and Autoimmunity: Novel Potential for Autoimmune Therapy

The Journal of Immunology (2017)

Jian Ye Yadan Wang Xia Liu Lingyun Li Adeleye Opejin

Abstract Innate regulation through TLR signaling has been shown to be important for promoting T cell subset development and function. However, limited information is known about whether differential TLR signaling can selectively inhibit Th17 and/or Th1 cells, which are important for controlling excessive inflammation and autoimmune responses. In this article, we demonstrate that activation of TLR7 signaling in T cells can inhibit Th17 cell differentiation from naive T cells and IL-17 production in established Th17 cells. We further report that downregulation of STAT3 signaling is responsible for TLR7-mediated inhibition of Th17 cells due to induction of suppressor of cytokine signaling 3 and 5. TLR7-mediated suppression of Th17 cells does not require dendritic cell involvement. In addition, we show that TLR7 signaling can suppress Th1 cell development and function through a mechanism different from Th17 cell suppression. Importantly, our complementary in vivo studies demonstrate that treatment with the TLR7 ligand imiquimod can inhibit Th1 and Th17 cells, resulting in the prevention of, and an immunotherapeutic reduction in, experimental autoimmune encephalomyelitis. These studies identify a new strategy to manipulate Th17/Th1 cells through TLR7 signaling, with important implications for successful immunotherapy against autoimmune and inflammatory diseases.

TLR7

10.4049/jimmunol.1601890

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Citations (32)