Positions

Overview

  • Lewis Shi received his MD in preventive medicine, MS in toxicology, and PhD in neurotoxicology. Upon graduation, he worked as a postdoctoral scholar at University of Wisconsin-Madison where he identified a novel role of the aryl hydrocarbon receptor (AhR) signaling in innate immune response against Listeria monocytogenes infection. He then joined St. Jude Children’s Research Hospital where he was among the first to show that the HIF-1a-glycolysis pathway functions as a metabolic checkpoint in reciprocal regulation of TH17 and iTreg, contributing to the establishment of the immune-metabolism field. While at St. Jude, he also demonstrated that the Gfi1-Foxo1 axis maintains the fidelity of genetic program of maturing T cells via a cell-autonomous mechanism and the Gfi1-IL-2 axis regulates the generation of nTreg cells by a non-cell autonomous mechanism.
    Prior to joining UAB, he served as an Assistant Professor at Case Western Reserve University and a non-tenure track faculty member at MD Anderson Cancer Center (MDACC). His previous work revealed the tumor cell-intrinsic resistance mechanism (loss of IFN-g signaling genes) as well as tumor cell-extrinsic resistance mechanism (upregulation of inhibitory molecules PD-L1 and VISTA in the tumor microenvironment) to anti-CTLA-4 therapy, the first immune checkpoint blockade (ICB) approved by FDA to treat cancer patients. Further, he uncovered a pivotal role of the interactive loop of IFN-g signaling and IL-7 signaling in T cells in dictating the therapeutic benefits of combined anti-CTLA-4 and anti-PD-1 therapy, a highly-pursued combination modality in cancer patients.
  • Selected Publications

    Academic Article

    Year Title Altmetric
    2020 Metabolic checkpoints in neurodegenerative T helper 17 (TH17) and neuroregenerative regulatory T (Treg) cells as new therapeutic targets for multiple sclerosis 2020
    2019 Predictive biomarkers for immune checkpoint blockade and opportunities for combination therapies 2019
    2019 Blockade of CTLA-4 and PD-1 Enhances adoptive T-cell therapy efficacy in an ICOS mediated manner. 2019
    2019 Metabolic regulation of T H 17 cells 2019
    2017 VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer 2017
    2017 Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes 2017
    2016 Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy 2016
    2016 Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy 2016
    2013 Gfi1: A unique controller of Treg cells 2013
    2013 Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells 2013
    2011 The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation 2011
    2011 Signaling by the phosphatase MKP-1 in dendritic cells imprints distinct effector and regulatory T cell fates 2011
    2011 HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells 2011
    2010 Bone marrow lymphoid and myeloid progenitor cells are suppressed in 7,12-dimethylbenz(a)anthracene (DMBA) treated mice 2010
    2009 Regulation of JNK and p38 MAPK in the immune system: Signal integration, propagation and termination 2009
    2009 Beta-naphthoflavone causes an AhR-independent inhibition of invasion and intracellular multiplication of Listeria monocytogenes in murine hepatocytes 2009
    2008 Use of Z310 cells as an in vitro blood-cerebrospinal fluid barrier model: Tight junction proteins and transport properties 2008
    2007 The aryl hydrocarbon receptor is required for optimal resistance to Listeria monocytogenes infection in mice 2007
    2007 Early lead exposure increases the leakage of the blood-cerebrospinal fluid barrier, in vitro 2007
    2005 Establishment of an in vitro brain barrier epithelial transport system for pharmacological and toxicological study 2005
    2005 Blood harmane concentrations and dietary protein consumption in essential tremor 2005

    Research Overview

  • Identifying novel targets to improve immune checkpoint blockers

    Our recent studies (Cell and Nature Communications, 2016) and previous reports demonstrated that immune checkpoint blockers (ICBs) (e.g., anti-CTLA-4) exert similar functional outcomes to those of common metabolic pathways (e.g., mTOR) (JEM and Immunity, 2011), i.e., promoting effector T cell (Teff) function (IFN-γ production) and depleting regulatory T cells (Treg). Interestingly, these effects are selectively induced in the tumor microenvironment , a special metabolic milieu with numerous features impacting the mTOR pathway. Given this key information, whether ICBs engage the mTOR pathways and its downstream targets in tumor-infiltrating T cell (TILs) is largely unknown and targeting these metabolic checkpoints as novel approaches to enhance therapeutic efficacy of ICBs remains to be explored. We will combine genetic mouse models with specific deletion of those genes in T cells, genetic manipulations with retroviral overexpression and CRISPR-CAS9 deletion, pharmacological approaches with metabolic inhibitors and activators, transplantable and orthotopic tumor models, and adoptive T-cell therapy (another promising modality in cancer immunotherapy) to evaluate therapeutic value of targeting these metabolic targets as a standalone therapy, or in combination with ICBs and conventional radiotherapy and chemotherapy. Further, we have an ongoing study showing that co-stimulatory molecule ICOS has an indispensable role in maintaining the survival and functionality of adoptively transferred tumor antigen-specific CD8+ T cells, especially when combined with ICBs. Currently, agonistic anti-ICOS therapeutic antibodies are being tested in Phase I clinical trials. Further mechanistic understanding will help guide these clinical trials and offer rationales to test additional combination therapies.

    Functional and transcriptional control of T cell development and differentiation

    The mTOR pathway is a master regulator for T cell metabolism, differentiation and function, with prominent roles in cancer, autoimmunity, and vaccination for infectious diseases. While the downstream targets of mTOR have been extensively studied, its upstream regulators are under-studied and an answer to which may offer potential therapeutic targets for various pathologies. Interestingly, TCR signaling regulates both Gfi1 expression and mTOR activity, suggesting Gfi1 and mTOR might crosstalk with each other. We will examine whether Gfi1 serves as an upstream regulator of the mTOR signaling. How the Gfi1-mTOR interaction dictates T cell development and acquisition of effector functions will be assessed using genetic mouse models and mouse autoimmune disease and tumor models. We recently showed that Gfi1 is required for anti-tumor immunity (PNAS, 2013) and for T cell maturation (PNAS, 2017). This study will offer new insights into whether mTOR pathway is the downstream link.
  • Full Name

  • Lewis Zhichang Shi