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

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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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Abstract B56: CXCR2 blockade reduces granulocytic myeloid cell compensation in response to macrophage targeted therapy and further enhances the efficacy of chemotherapy in pancreatic ductal adenocarcinoma

Cancer Immunology Research (2018)

Booyeon J. Han Tim M. Nywening Brian A. Belt Jian Ye William G. Hawkins

Abstract Background: The incidence of pancreatic ductal adenocarcinoma (PDAC) is rising, yet patient survival rates following conventional treatment remain abysmal. A unique feature of PDAC is the presence of a prominent tumor stroma with a dense network of fibrotic material and abundant inflammatory immune infiltrate. Bone marrow derived myeloid cells of both monocytic and granulocytic origin, including tumor associated macrophages (TAM) and neutrophils (TAN) respectively, are the most prevalent immune cells in the tumor microenvironment (TME) of PDAC. PDAC tumors co-opt chemokine signaling pathways to attract myeloid cells from the bone marrow to the TME where they suppress anti-tumor immune responses, support tumor progression, and confer resistance to therapy. In a previous clinical study, we demonstrated that targeted blockade of CCR2+ TAM with a small molecule CCR2 inhibitor (PF-04136309) nearly doubled responses to the FOLFIRINOX chemotherapy regimen in patients with locally advanced PDAC. Here, we show that tumor infiltrating CXCR2+ TAN compensate for TAM depletion in response to CCR2 blockade, so we hypothesized that dual targeting of both CCR2+ TAM and CXCR2+ TAN would further enhance chemotherapy efficacy for treating PDAC. Methods: Human blood, bone marrow, and tumor samples were acquired under an IRB approved protocol. PDAC cell lines (KCKO or KP) derived from spontaneous tumors were subcutaneously or orthotopically implanted into C57BL/6 mice. Tumor bearing mice were randomized and treated with vehicle, FOLFIRINOX, CCR2i (PF-04136309 or RS504393), CXCR2i (SB225002), CCR2i+CXCR2i, CCR2i+FOLFIRINOX, CXCR2i+FOLFIRINOX, or CCR2i+CXCR2i+FOLFIRINOX. Mice were sacrificed at fixed time points for tissue collection or followed for survival. Resected tissues were snap frozen for RNA extraction to perform qRT-PCR, fixed in formalin for histological staining and immunohistochemistry, or digested into single cell suspensions for flow cytometry analysis. Results: The prevalence of peripheral blood and bone marrow CXCR2+ TAN is prognostic in patients with PDAC. Tumors expressed elevated levels of the ELR+ chemokines including CXCL1, CXCL2, CXCL5, and CXCL8 and were infiltrated with significantly more CXCR2+ TAN compared to normal pancreas. Tumor expression of the ELR+ chemokines correlated with tumor infiltrating TAN and their levels were prognostic in human disease. Analysis of longitudinally paired tumor biopsies from patients treated with PF-04136309 had significantly increased levels of CXCR2+ TAN (p < 0.05). In mice, orthotopically implanted PDAC tumors significantly upregulated the ELR+ chemokines resulting in increased levels of CXCR2+ TAN in the peripheral blood, bone marrow, and TME compared to normal pancreas controls, recapitulating human disease. CXCR2i significantly decreased tumor infiltrating CXCR2+ TAN and reduced overall tumor burden. Single agent targeting of either TAM or TAN, using CCR2i or CXCR2i respectively, resulted in a compensatory influx of the other myeloid cell subset. However, dual targeting of both CCR2+ TAM and CXCR2+ TAN blocked myeloid compensation and further enhanced the efficacy of FOLFIRINOX. Dual CCR2/CXCR2 blockade reprogrammed the TME and generated a more robust anti-tumor T cell response compared to either agent alone. Conclusions: The ELR+ CXC/CXCR2 chemokine pathway plays a key role in PDAC tumor progression and CXCR2+ TAN compensation is observed with depletion of TAM in response to CCR2 blockade. Duel targeting of CCR2+ TAM and CXCR2+ TAN prevents myeloid plasticity to single agent therapy and further enhances the efficacy of chemotherapy. Thus, further studies exploring complementary immune targeting strategies are warranted in PDAC. Citation Format: Booyeon J. Han, Tim M. Nywening, Brian A. Belt, Jian Ye, William G. Hawkins, David G. DeNardo, David C. Linehan. CXCR2 blockade reduces granulocytic myeloid cell compensation in response to macrophage targeted therapy and further enhances the efficacy of chemotherapy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B56.

FOLFIRINOX

10.1158/2326-6074.tumimm17-b56

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Targeting gammadelta regulatory T cell recruitment for breast cancer immunotherapy (TUM2P.904)

The Journal of Immunology (2014)

Guangyong Peng Jian Ye Chunling Ma Eddy C. Hsueh Károly Tóth

Abstract Immunosuppressive microenvironments induced by regulatory T cells (Treg) present a major barrier for successful anti-tumor immunotherapy. Understanding the mechanisms for the accumulation of different subtypes of Treg cells in the immunosuppressive tumor microenvironment is essential to improving cancer treatment. Enriched gammadelta1 T cell populations in tumor-infiltrating lymphocytes (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 gammadelta Treg cells in breast cancer patients have yet to be elucidated. In this study, we showed that IP-10 secreted by breast cancer cells attracted gammadelta Treg cells. Using neutralizing antibodies against chemokines secreted by breast cancer cells, we found that IP-10 was the only functional chemokine that causes gammadelta Treg cells to migrate toward breast cancer cells. In a humanized NSG mouse model, human breast cancer cells attracted gammadelta Treg cells as revealed by a live cell imaging system. IP-10 neutralization in vivo inhibited migration and trafficking of gammadelta Treg cells into breast tumor sites, enhancing tumor immunity mediated by tumor-specific T cells. Together, our studies show how gammadelta Treg cells accumulate in breast tumors, providing a rationale for their immunological targeting to relieve immunosuppression in the tumor microenvironment.

Cancer Immunotherapy

Humanized mouse

10.4049/jimmunol.192.supp.71.28

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Controlling T cell senescence in the tumor microenvironment for tumor immunotherapy

OncoImmunology (2015)

Jian Ye Guangyong Peng

Understanding molecular mechanisms involved in creating and sustaining the tumor suppressive microenvironment is critical for the development of novel antitumor therapeutic strategies. We have identified the induction of T cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provided a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.

Senescence

Cancer Immunotherapy

10.4161/2162402x.2014.994398

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Tumor-Derived γδ Regulatory T Cells Suppress Innate and Adaptive Immunity through the Induction of Immunosenescence

The Journal of Immunology (2013)

Jian Ye Chunling Ma Eddy C. Hsueh Christopher S. Eickhoff Yanping Zhang

Fundamentally understanding the suppressive mechanisms used by different subsets of tumor-infiltrating regulatory T (Treg) cells is critical for the development of effective strategies for antitumor immunotherapy. γδ Treg cells have recently been identified in human diseases including cancer. However, the suppressive mechanisms and functional regulations of this new subset of unconventional Treg cells are largely unknown. In the current studies, we explored the suppressive mechanism(s) used by breast tumor-derived γδ Treg cells on innate and adaptive immunity. We found that γδ Treg cells induced immunosenescence in the targeted naive and effector T cells, as well as dendritic cells (DCs). Furthermore, senescent T cells and DCs induced by γδ Treg cells had altered phenotypes and impaired functions and developed potent suppressive activities, further amplifying the immunosuppression mediated by γδ Treg cells. In addition, we demonstrated that manipulation of TLR8 signaling in γδ Treg cells can block γδ Treg-induced conversion of T cells and DCs into senescent cells in vitro and in vivo. Our studies identify the novel suppressive mechanism mediated by tumor-derived γδ Treg cells on innate and adaptive immunity, which should be critical for the development of strong and innovative approaches to reverse the tumor-suppressive microenvironment and improve effects of immunotherapy.

Cancer Immunotherapy

10.4049/jimmunol.1202369

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CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome

Oncotarget (2015)

Yi Huang Chunling Ma Qunyuan Zhang Jian Ye Fang Wang

// Yi Huang 1,2,* , Chunling Ma 1,3,4,* , Qunyuan Zhang 5 , Jian Ye 1 , Fang Wang 1,6 , Yanping Zhang 7 , Pamela Hunborg 7 , Mark A. Varvares 8 , Daniel F. Hoft 1 , Eddy C. Hsueh 7 and Guangyong Peng 1 1 Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA 2 Center for Clinical Molecular Medicine, Children’s Hospital of Chongqing Medical University, Chongqing, P. R. China 3 Department of Laboratory Medicine, Women and Children’s Health Care Hospital of Linyi City, Linyi, P. R. China 4 Molecular Biology Experimental Center, Shandong Medical College, Linyi, P. R. China 5 Department of Genetics, Washington University School of Medicine in St. Louis, Saint Louis, MO, USA 6 Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China 7 Department of Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA 8 Department of Otolaryngology-Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA * These authors are contributed equally to this work Correspondence to: Eddy C. Hsueh, email: // Guangyong Peng, email: // Keywords : CD4 + T cells; CD8 + T cells; regulatory T cells; Th17 cells; breast tumor microenvironment Received : February 11, 2015 Accepted : April 09, 2015 Published : April 29, 2015 Abstract The Cancer Immunoediting concept has provided critical insights suggesting dual functions of immune system during the cancer initiation and development. However, the dynamics and roles of CD4 + and CD8 + T cells in the pathogenesis of breast cancer remain unclear. Here we utilized two murine breast cancer models (4T1 and E0771) and demonstrated that both CD4 + and CD8 + T cells were increased and involved in immune responses, but with distinct dynamic trends in breast cancer development. In addition to cell number increases, CD4 + T cells changed their dominant subsets from Th1 in the early stages to Treg and Th17 cells in the late stages of the cancer progression. We also analyzed CD4 + and CD8 + T cell infiltration in primary breast cancer tissues from cancer patients. We observed that CD8 + T cells are the key effector cell population mediating effective anti-tumor immunity resulting in better clinical outcomes. In contrast, intra-tumoral CD4 + T cells have negative prognostic effects on breast cancer patient outcomes. These studies indicate that CD4 + and CD8 + T cells have opposing roles in breast cancer progression and outcomes, which provides new insights relevant for the development of effective cancer immunotherapeutic approaches.

Immunoediting

Tumor progression

10.18632/oncotarget.3958

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Citations (196)

TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy

Cell Metabolism (2018)

Lingyun Li Xia Liu Katherine L. Sanders James L. Edwards Jian Ye

Reprogramming

Cancer Immunotherapy

Adoptive Cell Transfer

10.1016/j.cmet.2018.09.020

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Citations (187)

Human tumor-infiltrating Th17 cells have the capacity to differentiate into IFN-gamma+ and FOXP3+ T cells with potent suppressive function (66.27)

The Journal of Immunology (2011)

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

Abstract Accumulating evidence suggests that T-helper 17 (Th17) cells and regulatory T (Treg) cells may exhibit development plasticity, and that CD4+ Tregs can differentiate into IL-17-producing T cells; however, whether Th17 cells can reciprocally convert into Tregs has not been described. In this study, we generated Th17 clones from tumor-infiltrating T lymphocytes (TILs). We showed that Th17 clones generated from TILs 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 Tregs. We further demonstrated that the Th17-derived Tregs, unlike naturally occurring CD4+CD25+ Tregs, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human tumor-infiltrating Th17 cells can differentiate into Tregs and indicate a substantial developmental plasticity of Th17 cells.

Reprogramming

10.4049/jimmunol.186.supp.66.27

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Correction to: SALL1 functions as a tumor suppressor in breast cancer by regulating cancer cell senescence and metastasis through the NuRD complex

Molecular Cancer (2022)

Chunling Ma Fang Wang Bing Han Xiaoli Zhong Fusheng Si

Senescence

10.1186/s12943-022-01554-4

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Interverntion effect analysis of sexual and reproductive health of migrant unmarried male workers

Journal of Medical Forum (2011)

Jian Ye

Objective To evaluate the effect of compositive intervence on migrant unmarried male workers in Nanshan district,which related to awareness rate of knowledge about sexual and reproductive health and health-seeking behavior,and provide the new thought of the service mode for reproductive health of unmarried workers.Methods To carry out an baseline investigation on migrant unmarried male laborers which all come from 4 factories that are randomly selected in Majialong community of Shenzhen,and implement the comprehensive intervention plan base on the analysis of investigation.Do the investigation again next year to get the facts.Results ①They can answer 90% of sex knowledge question,they made remarkable progress than before(P0.05);②The rate that take contraception measures in sexual act is increased proportionably,especially the usage rate of condom rise from 70.16% to 96.04%(P0.05);③Ratio of premarital sex fall to 60.7%,and attitude to sex has a clearly change.④ The ratio of sex partner unwilling pregnancy to premarital sex is 9.0%,and all of the unwilling pregnancy cases take termination of pregnancy in the family-planning service center.⑤ The rate of urinary micturition and urethra disease is fall from 4.68% to 1.29% when take medical treatment after compositive intervence.Conclusions Blend propaganda and education of planned parenthood with technical service into corporate culture,and accepted by corporate and workers.It will be helpful to improve sexual and reproductive health level of migrant unmarried male laborers.

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Molecular control of human regulatory T cell suppression for tumor immunotherapy (P2106)

The Journal of Immunology (2013)

Guangyong Peng Jian Ye Eddy C. Hsueh Qunyuan Zhang Chunling Ma

Abstract Immunotherapy is a promising approach for treating patients with malignant tumor, but immunosuppressive microenvironments induced by regulatory T cells (Tregs) present a major barrier to successful anti-tumor immunotherapy. A better understanding of the suppressive mechanisms utilized by Tregs is essential for the development of novel strategies to treat human cancer. Here we report that human Tregs can induce senescence in responder naïve and effector T cells in vitro and in vivo. Senescent responder T cells induced by human Tregs changed their phenotypes and cytokine profiles, and possessed potent suppressive function. Furthermore, Treg-mediated molecular control of senescence in responder T cells was associated with selective modulation of p38 and ERK1/2 signaling and cell cycle regulatory molecules p16, p21 and p53. We further revealed that human Treg-induced senescence and suppressor function could be blocked by TLR8 signaling and/or by specific ERK1/2 and p38 inhibition in vitro and in vivo in animal models. Our studies identify a novel mechanism of human Treg cell suppression that induces targeted responder T cell senescence, and provide new insights relevant for the development of strategies capable of preventing and/or reversing Treg-induced immune suppression for tumor immunotherapy.

Senescence

Cancer Immunotherapy

Regulatory T cell

10.4049/jimmunol.190.supp.132.43

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