Haiyan S. Li
University of Texas MD Anderson Cancer Center
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Publication
Featured researches published by Haiyan S. Li.
Cancer Discovery | 2016
Weiyi Peng; Jie Qing Chen; Chengwen Liu; Shruti Malu; Caitlin Creasy; Michael T. Tetzlaff; Chunyu Xu; Jodi A. McKenzie; Chunlei Zhang; Xiaoxuan Liang; Leila Williams; Wanleng Deng; Guo Chen; Rina M. Mbofung; Alexander J. Lazar; Carlos A. Torres-Cabala; Zachary A. Cooper; Pei-Ling Chen; Trang Tieu; Stefani Spranger; Xiaoxing Yu; Chantale Bernatchez; Marie-Andree Forget; Cara Haymaker; Rodabe N. Amaria; Jennifer L. McQuade; Isabella C. Glitza; Tina Cascone; Haiyan S. Li; Lawrence N. Kwong
UNLABELLED T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death. Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti-PD-1 and anti-CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K-AKT pathway inhibitors. SIGNIFICANCE This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K-AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K-AKT pathway to increase the efficacy of immunotherapy.
Clinical Cancer Research | 2013
Chengwen Liu; Weiyi Peng; Chunyu Xu; Yanyan Lou; Minying Zhang; Jennifer A. Wargo; Jie Qing Chen; Haiyan S. Li; Stephanie S. Watowich; Yan Yang; Dennie T. Frederick; Zachary A. Cooper; Rina M. Mbofung; Mayra Whittington; Keith T. Flaherty; Scott E. Woodman; Michael A. Davies; Laszlo Radvanyi; Willem W. Overwijk; Gregory Lizée; Patrick Hwu
Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAF-mutant tumors. Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen–independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model. Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell–based immunotherapy for the treatment of patients with melanoma. Clin Cancer Res; 19(2); 393–403. ©2012 AACR.
Nature Immunology | 2011
Cliff Y Yang; J. Adam Best; Jamie Knell; Edward Yang; Alison D Sheridan; Adam K Jesionek; Haiyan S. Li; Richard Rivera; Kristin Camfield Lind; Louise M. D'Cruz; Stephanie S. Watowich; Cornelis Murre; Ananda W. Goldrath
During infection, naive CD8+ T cells differentiate into effector cells, which are armed to eliminate pathogens, and memory cells, which are poised to protect against reinfection. The transcriptional program that regulates terminal differentiation into short-lived effector-memory versus long-lived memory cells is not clearly defined. Through the use of mice expressing reporters for the DNA-binding inhibitors Id2 and Id3, we identified Id3hi precursors of long-lived memory cells before the peak of T cell population expansion or upregulation of cell-surface receptors that indicate memory potential. Deficiency in Id2 or Id3 resulted in loss of distinct CD8+ effector and memory populations, which demonstrated unique roles for these inhibitors of E-protein transcription factors. Furthermore, cytokines altered the expression of Id2 and Id3 differently, which provides insight into how external cues influence gene expression.
Journal of Biological Chemistry | 2012
Roza Nurieva; Andrew Podd; Yuhong Chen; Andrei Alekseev; Mei Yu; Xiaopeng Qi; Hua Huang; Renren Wen; Junmei Wang; Haiyan S. Li; Stephanie S. Watowich; Hai Qi; Chen Dong; Demin Wang
Background: Tfh cells regulate B cell-mediated humoral immunity. Results: STAT5 regulated Blimp-1 expression, and STAT5 deficiency in CD4+ T cells resulted in an increase of Tfh generation and an impairment of B cell tolerance. Conclusion: STAT5 negatively regulates Tfh development by up-regulating Blimp-1 and thus controls the humoral immunity and B cell tolerance. Significance: These findings may help to find new ways to treat antibody-mediated autoimmune diseases. Recent work has identified a new subset of CD4+ T cells named as Tfh cells that are localized in germinal centers and critical in germinal center formation. Tfh cell differentiation is regulated by IL-6 and IL-21, possibly via STAT3 factor, and B cell lymphoma 6 (Bcl6) is specifically expressed in Tfh cells and required for their lineage specification. In the current study, we characterized the role of STAT5 in Tfh cell development. We found that a constitutively active form of STAT5 effectively inhibited Tfh differentiation by suppressing the expression of Tfh-associated factors (CXC motif) receptor 5 (CXCR5), musculoaponeurotic fibrosarcoma (c-Maf), Bcl6, basic leucine zipper transcription factor ATF-like (Batf), and IL-21, and STAT5 deficiency greatly enhanced Tfh gene expression. Importantly, STAT5 regulated the expression of Tfh cell suppressor factor B lymphocyte-induced maturation protein 1 (Blimp-1); STAT5 deficiency impaired Blimp-1 expression and resulted in elevated expression of Tfh-specific genes. Similarly, inhibition of IL-2 potentiated Tfh generation, associated with dampened Blimp-1 expression; Blimp-1 overexpression inhibited Tfh gene expression in Stat5-deficient T cells, suggesting that the IL-2/STAT5 axis functions to regulate Blimp-1 expression. In vivo, deletion of STAT5 in CD4+ T cells resulted in enhanced development of Tfh cells and germinal center B cells and led to an impairment of B cell tolerance in a well defined mouse tolerance model. Taken together, this study demonstrates that STAT5 controls Tfh differentiation.
Blood | 2010
Hoainam Nguyen-Jackson; Athanasia D. Panopoulos; Huiyuan Zhang; Haiyan S. Li; Stephanie S. Watowich
Neutrophil mobilization, the release of neutrophils from the bone marrow reserve into circulating blood, is important to increase peripheral neutrophil amounts during bacterial infections. Granulocyte colony-stimulating factor (G-CSF) and chemokines, such as macrophage-inflammatory protein-2 (MIP-2; CXCL2), can induce neutrophil mobilization, but the mechanism(s) they use remain unclear. Signal transducers and activator of transcription 3 (STAT3) is the principal intracellular signaling molecule activated upon G-CSF ligation of its receptor. Using a murine model with conditional STAT3 deletion in bone marrow, we demonstrated previously that STAT3 regulates acute G-CSF-responsive neutrophil mobilization and MIP-2-dependent neutrophil chemotaxis. In this study, we show STAT3 is also necessary for MIP-2-elicited neutrophil mobilization. STAT3 appears to function by controlling extracellular signal-regulated kinase (ERK) activation, which is important for MIP-2-mediated chemotaxis. In addition, we demonstrate that G-CSF stimulates the expression of the MIP-2 receptor via STAT3-dependent transcriptional activation of Il8rb. G-CSF treatment also induces STAT3-dependent changes in bone marrow chemokine expression levels which may further affect neutrophil retention and release. Taken together, our study demonstrates that STAT3 regulates multiple aspects of chemokine and chemokine receptor expression and function within the bone marrow, indicating a central role in the neutrophil mobilization response.
Nature Immunology | 2014
Qiang Zou; Jin Jin; Hongbo Hu; Haiyan S. Li; Simona Romano; Yichuan Xiao; Mako Nakaya; Xiaofei Zhou; Xuhong Cheng; Peirong Yang; Guillermina Lozano; Chengming Zhu; Stephanie S. Watowich; Stephen E. Ullrich; Shao Cong Sun
Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.
Blood | 2012
Haiyan S. Li; Cliff Y Yang; Kalyan C. Nallaparaju; Huiyuan Zhang; Yong-Jun Liu; Ananda W. Goldrath; Stephanie S. Watowich
Cytokines and transcription factors play key roles in dendritic cell (DC) development, yet information about regulatory interactions between these signals remains limited. Here we show that the cytokines GM-CSF and Flt3L induce the transcriptional mediators Id2 and E2-2 and control DC lineage diversification by STAT-dependent pathways. We found that STAT5 is required for tissue CD103(+) DC generation and plasmacytoid DC (pDC) suppression in steady state or response to GM-CSF. STAT5 stimulates GM-CSF-dependent expression of Id2, which controls CD103(+) DC production and pDC inhibition. By contrast, pDCs, but not CD103(+) DCs, are dependent on STAT3. Consistently, STAT3 stimulates Flt3L-responsive expression of the pDC regulator Tcf4 (E2-2). These data suggest that STATs contribute to DC development by controlling transcription factors involved in lineage differentiation.
Cytokine & Growth Factor Reviews | 2016
Emily J. Hillmer; Huiyuan Zhang; Haiyan S. Li; Stephanie S. Watowich
The transcriptional regulator STAT3 has key roles in vertebrate development and mature tissue function including control of inflammation and immunity. Mutations in human STAT3 associate with diseases such as immunodeficiency, autoimmunity and cancer. Strikingly, however, either hyperactivation or inactivation of STAT3 results in human disease, indicating tightly regulated STAT3 function is central to health. Here, we attempt to summarize information on the numerous and distinct biological actions of STAT3, and highlight recent discoveries, with a specific focus on STAT3 function in the immune and hematopoietic systems. Our goal is to spur investigation on mechanisms by which aberrant STAT3 function drives human disease and novel approaches that might be used to modulate disease outcome.
Blood | 2011
Haiyan S. Li; Alexander Gelbard; Gustavo J. Martinez; Eiji Esashi; Huiyuan Zhang; Hoainam Nguyen-Jackson; Yong-Jun Liu; Willem W. Overwijk; Stephanie S. Watowich
Plasmacytoid dendritic cells (pDCs) reside in bone marrrow and lymphoid organs in homeostatic conditions and typically secrete abundant quantities of type I interferons (IFNs) on Toll-like receptor triggering. Recently, a pDC population was identified within Peyer patches (PPs) of the gut that is distinguished by its lack of IFN production; however, the relationship of PP pDCs to pDCs in other organs has been unclear. We report that PP pDCs are derived from common DC progenitors and accumulate in response to Fms-like tyrosine kinase 3 ligand, yet appear divergent in transcription factor profile and surface marker phenotype, including reduced E2-2 and CCR9 expression. Type I IFN signaling via STAT1 has a cell-autonomous role in accrual of PP pDCs in vivo. Moreover, IFN-α enhances pDC generation from DC progenitors by a STAT1-dependent mechanism. pDCs that have been developed in the presence of IFN-α resemble PP pDCs, produce inflammatory cytokines, stimulate Th17 cell generation, and fail to secrete IFN-α on Toll-like receptor engagement. These results indicate that IFN-α influences the development and function of pDCs by inducing emergence of an inflammatory (Th17-inducing) antigen-presenting subset, and simultaneously regulating accumulation of pDCs in the intestinal microenvironment.
PLOS ONE | 2012
Haiyan S. Li; Nathaniel R. Greeley; Naoshi Sugimoto; Yong-Jun Liu; Stephanie S. Watowich
MicroRNAs (miRNAs) have emerged as critical regulators of many cellular responses, through the action of miRNA-induced silencing complex (miRISC)- or miRNA ribonucleoprotein complex (miRNP)-mediated gene repression. Here we studied the role of miRNAs in the development of dendritic cells (DCs), an important immune cell type that is divided into conventional DC (cDC) and plasmacytoid DC (pDC) subsets. We found that miR-22 was highly expressed in mouse CD11c+ CD11b+ B220− cDCs compared to pDCs, and was induced in DC progenitor cell cultures with GM-CSF, which stimulate CD11c+ CD11b+ B220− cDC differentiation. Enforced overexpression of miR-22 during DC development enhanced CD11c+ CD11b+ B220− cDC generation at the expense of pDCs, while miR-22 knockdown demonstrated opposite effects. Moreover, overexpression and knockdown of miR-22 showed significant effects on the mRNA abundance of Irf8, which encodes the transcription factor IRF8 that plays essential roles in DC development. Luciferase reporter assays confirmed that miR-22 binds directly to the 3′UTR of the mouse Irf8 mRNA. Collectively, these results suggest that miR-22 targets Irf8 mRNA for posttranscriptional repression and controls DC subset differentiation.