Lewis Shi received his MD in preventive medicine and MS in toxicology from China. He then obtained his PhD from Purdue University. 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 Case Western Reserve University, he served as a faculty member at MD Anderson Cancer Center (MDACC). His work at MDACC 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.
Research Information
Research Projects
Recent approvals of ICBs (anti-CTLA-4, anti-PD-1, and anti-PD-L1) by FDA have rejuvenated the field of cancer immunotherapy. However, accumulating data indicate that only a subset of cancer patients benefit from these treatments, warranting further research endeavors to discover novel targets for cancer interventions. Moreover, severe immune-related adverse events (irAEs) have been observed in a decent proportion of patients treated with ICBs, leading to the early termination of otherwise effective ICBs. Thus, tampering irAEs would unequivocally improve the utilization of ICBs in cancer patients.
My research focuses on understanding the mechanisms of immune signaling, metabolic processes, and transcriptional factors that control the maintenance, survival and function of T cells, a central effector cell type in anti-tumor immunity induced by ICBs. For immune signaling, we are interested in IFN-g, IL-17 and IL-7 pathways that orchestrate the formation of effector (TH1 and TH17) and memory T cells (TEM and TCM). For cell metabolic control of T cell differentiation and function, we are interested in the mTOR-HIF1a-glycolysis axis. Information gained from these mechanistic studies could manifest legitimate therapeutic/prophylactic means to mitigate irAEs, and could also reveal potential “metabolic checkpoints” that can be combined with immune checkpoints to boost anti-tumor efficacy.
Our experimental approaches include mouse genetics, cellular immunology and biochemistry, as well as murine models of autoimmunity, inflammation, infectious diseases and cancer. Through close collaboration with clinicians at Case Western Reserve University, University Hospitals, and Cleveland Clinic, we are testing the translational potentials of our preclinical findings.
Publications
Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, Zhao H, Chen J, Chen H, Efstathiou E, Troncoso P, Allison JP, Logothetis CJ, Wistuba II, Sepulveda MA, Sun J, Wargo J, Blando J, Sharma P. (2017).VISTA as an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nature Medicine 2017 Mar 27. doi: 10.1038/nm.4308. [Epub ahead of print].
Shi LZ*, Saravia J*, Zeng H, Kalupahana NS, Guy C, Neale G, Chi H (2016, in press). Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes. Proc Natl Acad Sci U S A (*: equal contribution).
Gao J*, Shi LZ*, Zhao H*, Chen J, XiongL, He Q, Chen T, Roszik J, Bernatchez C, WoodmanSE, Chen PL, Hwu P, Allison JP, Futreal A, Wargo JA, Sharma P (2016). Loss of IFN-g pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell pii: S0092-8674(16): 31167-9. (highlighted by Nature Reviews Clinical Oncology) (*: equal contribution).
Shi LZ, Fu T*, Guan B, Chen J, Blando JM, Allison JP, Xiong L, Subudhi SK, Gao J, Sharma P (2016). Interdependent IL-7 and IFN-γ Signaling in T-Cell Controls Tumor Eradication by Combined α-CTLA-4+α-PD-1 Therapy. Nature Communications 7(12335): 1-12. (*: equal contribution).
Shi LZ, Kalupahana NS, Turnis ME, Neale G, Hock H, Vignali DA, Chi H (2013). Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells. Proc Natl Acad Sci U S A 110(34): E3198-205.
Shi LZ, Chi H (2013). Gfi1: a unique controller of T(reg) cells. Cell Cycle12(23): 3581-2.
Shi LZ*, Wang R*, Huang G, Vogel P, Neale G, Green DR, and Chi H (2011). Hif1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. Journal of Experimental Medicine 208(7): 1367-76. (highlighted by Nature Reviews Immunology and Nature Medicine) (*: equal contribution). [cited more than 600 times since publication]
Wang R, Dillon CP*, Shi LZ*, Milasta S, Carter R, McCormick LL, Fitzgerald P,Chi H, Munger J and Green DR (2011). The transcription factor The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.. Immunity 35(6): 871-82 (*: equal contribution). [cited more than 550 times since publication]
Huang G, Wang Y, Shi LZ, Kanneganti TD, and Chi H (2011). Signaling by the phosphatase MKP-1 in dendritic cells imprints distinct effector and regulatory T cell fates.. Immunity 35(1): 45-58.
Huang G, Shi LZ, and Chi H (2009). Regulation of JNK and p38 MAPK in the immune system: signal integration, propagation and termination. (review) Cytokine 48(3): 161-9.