Zhibin Chen
University of Miami
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Publication
Featured researches published by Zhibin Chen.
Frontiers in Immunology | 2014
Kevin H. Toomer; Zhibin Chen
Cancer immunotherapy through manipulation of the immune system holds great potential for the treatment of human cancers. However, recent trials targeting the negative immune regulators cytotoxic T-lymphocyte antigen 4, programed death 1 (PD-1), and PD-1 receptor ligand (PD-L1) demonstrated that clinically significant antitumor responses were often associated with the induction of autoimmune toxicity. This finding suggests that the same immune mechanisms that elicit autoimmunity may also contribute to the destruction of tumors. Given the fact that the immunological identity of tumors might be largely an immunoprivileged self, autoimmunity may not represent a wholly undesirable outcome in the context of cancer immunotherapy. Rather, targeted killing of cancer cells and autoimmune damage to healthy tissues may be intricately linked through molecular mechanisms, in particular inflammatory cytokine signaling. On the other hand, since chronic inflammation is a well-recognized condition that promotes tumor development, it appears that autoimmunity can be a “double agent” in mediating either pro-tumor or antitumor effects. This review surveys the tumor-promoting and tumoricidal activities of several prominent cytokines: IFN-γ, TNF-α, TGF-β, IL-17, IL-23, IL-4, and IL-13, produced by three major subsets of T helper cells that interact with innate immune cells. Many of these cytokines exert divergent and seemingly contradictory effects on cancer development in different human and animal models, suggesting a high degree of context dependence in their functions. We hypothesize that these inflammatory cytokines could mediate a feedback loop of autoimmunity, antitumor immunity, and tumorigenesis. Understanding the diverse and paradoxical roles of cytokines from autoimmune responses in the setting of cancer will advance the long-term goal of improving cancer immunotherapy, while minimizing the hazards of immune-mediated tissue damage and the possibility of de novo tumorigenesis, through proper monitoring and preventive measures.
Breast Cancer Research and Treatment | 2016
Tulay Koru-Sengul; Ana M. Santander; Feng Miao; Lidia Sanchez; Merce Jorda; Stefan Glück; Tan A. Ince; Mehrad Nadji; Zhibin Chen; Manuel L. Penichet; Margot P. Cleary; Marta Torroella-Kouri
Abstract Racial disparities in breast cancer incidence and outcome are a major health care challenge. Patients in the black race group more likely present with an early onset and more aggressive disease. The occurrence of high numbers of macrophages is associated with tumor progression and poor prognosis in solid malignancies. Macrophages are observed in adipose tissues surrounding dead adipocytes in “crown-like structures” (CLS). Here we investigated whether the numbers of CD163+ tumor-associated macrophages (TAMs) and/or CD163+ CLS are associated with patient survival and whether there are significant differences across blacks, non-black Latinas, and Caucasians. Our findings confirm that race is statistically significantly associated with the numbers of TAMs and CLS in breast cancer, and demonstrate that the highest numbers of CD163+ TAM/CLS are found in black breast cancer patients. Our results reveal that the density of CD206 (M2) macrophages is a significant predictor of progression-free survival univariately and is also significant after adjusting for race and for HER2, respectively. We examined whether the high numbers of TAMs detected in tumors from black women were associated with macrophage proliferation, using the Ki-67 nuclear proliferation marker. Our results reveal that TAMs actively divide when in contact with tumor cells. There is a higher ratio of proliferating macrophages in tumors from black patients. These findings suggest that interventions based on targeting TAMs may not only benefit breast cancer patients in general but also serve as an approach to remedy racial disparity resulting in better prognosis patients from minority racial groups.
Clinical and Experimental Immunology | 2012
Dongmei Han; Xiaodong Cai; Ji Wen; D. Matheson; J. S. Skyler; Norma S. Kenyon; Zhibin Chen
The mRNA levels of a set of immune‐related genes were analysed with peripheral blood samples from at‐risk, new‐onset and long‐term type 1 diabetes (T1D) patients, in comparison to those from healthy controls. The selected set includes T lymphocyte genes [CD3G and cytotoxic T lymphocyte‐associated antigen 4 (CTLA4)], B lymphocyte genes (CD19 and CD20) and myeloid cell‐related genes [CD11b, Toll‐like receptor (TLR)‐9, arginase (ARG1)]. Also included is a subset of the S100 family members that has been documented recently as regulatory elements of innate immunity. Samples from patients with long‐term T1D had a reduced level of mRNA for most of selected innate and adaptive immune genes. No such reduction was detected in samples collected from at‐risk or new‐onset T1D patients. Analyses of regulatory gene expression ratios revealed a dynamic disproportion of CTLA4 versus CD3G expression in samples from at‐risk, new‐onset and long‐term T1D patients. These changes could serve as immunological biomarkers for the status of the immune system during T1D progression and therapeutic interventions.
Frontiers in Immunology | 2012
Dongmei Han; Xiaodong Cai; Ji Wen; Norma S. Kenyon; Zhibin Chen
Dysregulated expression of key immune genes may cause breakdown of immunological tolerance and development of autoimmune disorders such as type 1 diabetes (T1D). General immune insufficiencies have also been implicated as a trigger of autoimmunity, due to their potential impact on immune homeostasis. Recent studies have detected evidence of systemic reduction in immune gene expression in long-term diabetic patients but the changes were not present before or at T1D onset. The changes could not be merely correlated with alteration in metabolic parameters. The studies also identified a dynamic expression pattern of several well-known as well as little-studied, immune-related genes during the course of T1D. An intriguing “ratio profile” of immune regulatory genes, such as CTLA4 and members of the S100 family, versus “baseline” immune genes, such as CD3G, prompted us to further examine immune gene expression relationships for a set of molecules representing T cells, B cells, and myeloid cells. No evidence was found to suggest an overall breach of tolerance equilibrium in T1D. Perplexingly, patients with long-term T1D presented a gene expression profile that was surprisingly more coordinated in analyses of “networking” relationship. Computational analyses of the “ratio profiles” or “relationship profiles” of immune gene expression might provide a clue for further studies of immunobiology in human T1D and other autoimmune diseases, as to how the profiles may be related to the pathogenic cause of the disease, to the effect of the diseases on immune homeostasis, or to an immunological process associated with the course of the diseases but is neither a direct cause nor a direct effect of the diseases.
PLOS ONE | 2013
Ji Wen; Zhibin Chen; Xiaodong Cai
Alternative splicing (AS) of precursor mRNA (pre-mRNA) is a crucial step in the expression of most eukaryotic genes. Splicing factors (SFs) play an important role in AS regulation by binding to the cis-regulatory elements on the pre-mRNA. Although many splicing factors (SFs) and their binding sites have been identified, their combinatorial regulatory effects remain to be elucidated. In this paper, we derive a biophysical model for AS regulation that integrates combinatorial signals of cis-acting splicing regulatory elements (SREs) and their interactions. We also develop a systematic framework for model inference. Applying the biophysical model to a human RNA-Seq data set, we demonstrate that our model can explain 49.1%–66.5% variance of the data, which is comparable to the best result achieved by biophysical models for transcription. In total, we identified 119 SRE pairs between different regions of cassette exons that may regulate exon or intron definition in splicing, and 77 SRE pairs from the same region that may arise from a long motif or two different SREs bound by different SFs. Particularly, putative binding sites of polypyrimidine tract-binding protein (PTB), heterogeneous nuclear ribonucleoprotein (hnRNP) F/H and E/K are identified as interacting SRE pairs, and have been shown to be consistent with the interaction models proposed in previous experimental results. These results show that our biophysical model and inference method provide a means of quantitative modeling of splicing regulation and is a useful tool for identifying SREs and their interactions. The software package for model inference is available under an open source license.
Science Signaling | 2017
Connor J. Dwyer; Allison L. Bayer; Carmen Fotino; Liping Yu; Cecilia Cabello-Kindelan; Natasha C. Ward; Kevin H. Toomer; Zhibin Chen; Thomas R. Malek
Reducing IL-2 signaling in T cells results in accelerated diabetes in mice due to defective regulatory T cell function. IL-2 signaling and autoimmunity Regulatory T cells (Tregs) suppress autoreactive effector T cells to prevent the occurrence of autoimmune diseases, such as type 1 diabetes (T1D). The cytokine interleukin-2 (IL-2) is critical for the development and homeostasis of Treg subsets. Polymorphisms in the genes encoding IL-2 and its receptor subunits are associated with an increased risk of developing autoimmunity. To examine the effect of decreased IL-2 signaling, Dwyer et al. expressed a signaling-defective mutant IL-2 receptor (IL-2RβY3) in T cells in NOD mice, a model of T1D. Compared to NOD mice expressing wild-type IL-2Rβ, those expressing IL-2RβY3 in their T cells had accelerated onset of T1D. This was associated with a decrease in the numbers and suppressive activity of different Treg subsets and in the infiltration of autoreactive effector T cells into the pancreas. Together, these data suggest that the use of low-dose IL-2 to therapeutically modulate different Treg subsets in the context of autoimmune disease should be evaluated. The cytokine interleukin-2 (IL-2) is critical for the functions of regulatory T cells (Tregs). The contribution of polymorphisms in the gene encoding the IL-2 receptor α subunit (IL2RA), which are associated with type 1 diabetes, is difficult to determine because autoimmunity depends on variations in multiple genes, where the contribution of any one gene product is small. We investigated the mechanisms whereby a modest reduction in IL-2R signaling selectively in T lymphocytes influenced the development of diabetes in the NOD mouse model. The sensitivity of IL-2R signaling was reduced by about two- to threefold in Tregs from mice that coexpressed wild-type IL-2Rβ and a mutant subunit (IL-2RβY3) with reduced signaling (designated NOD-Y3). Male and female NOD-Y3 mice exhibited accelerated diabetes onset due to intrinsic effects on multiple activities in Tregs. Bone marrow chimera and adoptive transfer experiments demonstrated that IL-2RβY3 Tregs resulted in impaired homeostasis of lymphoid-residing central Tregs and inefficient development of highly activated effector Tregs and that they were less suppressive. Pancreatic IL-2RβY3 Tregs showed impaired development into IL-10–secreting effector Tregs. The pancreatic lymph nodes and pancreases of NOD-Y3 mice had increased numbers of antigen-experienced CD4+ effector T cells, which was largely due to impaired Tregs, because adoptively transferred pancreatic autoantigen–specific CD4+ Foxp3− T cells from NOD-Y3 mice did not accelerate diabetes in NOD.SCID recipients. Our study indicates that the primary defect associated with chronic, mildly reduced IL-2R signaling is due to impaired Tregs that cannot effectively produce and maintain highly functional tissue-seeking effector Treg subsets.
Journal of Experimental Medicine | 2018
Jason Miska; Jen Bon Lui; Kevin H. Toomer; Priyadharshini Devarajan; Xiaodong Cai; JeanMarie Houghton; Diana M. Lopez; Maria T. Abreu; Gaofeng Wang; Zhibin Chen
Genetically predisposed CTLA4 insufficiency in humans is associated with gastric cancer development, which is paradoxical to the prototypical role of CTLA4 in suppressing antitumor immunity. CTLA4 is a critical immune checkpoint against autoimmune disorders. Autoimmunity has been implicated in protumor or antitumor activities. Here, we show that CTLA4 insufficiency initiates de novo tumorigenesis in the mouse stomach through inflammation triggered by host-intrinsic immune dysregulation rather than microbiota, with age-associated progression to malignancy accompanied by epigenetic dysregulation. The inflammatory tumorigenesis required CD4 T cells, but not the TH1 or TH17 subsets. Deficiencies in IL-4 and IL-13 or IL-4 receptor &agr; broke the link between inflammation and initiation of tumorigenesis. This study establishes the causality of CTLA4 insufficiency in gastric cancer and uncovers a role of type 2 inflammation in initiating gastric epithelial transformation. These findings suggest possible improvement of immune therapies by blocking tumorigenic type 2 inflammation while preserving antitumor type 1 immunity.
Breast Cancer Research and Treatment | 2015
Ji Wen; Kevin H. Toomer; Zhibin Chen; Xiaodong Cai
Cell Reports | 2015
Jen Bon Lui; Priyadharshini Devarajan; Sarah A. Teplicki; Zhibin Chen
Journal of Cell Biology | 2014
Miska Jason; Midhat H. Abdulreda; Priyadharshini Devarajan; Jen Bon Lui; Jun Suzuki; Antonello Pileggi; Per-Olof Berggren; Zhibin Chen