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Zihai Li | |
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Zihai Li (born July 1964) is a board-certified medical oncologist, cancer immunologist, and leader in academic medicine. He was recruited to Ohio State University Comprehensive Cancer Center – The James Cancer Hospital & Solove Research Institute (OSUCCC) in 2019 as the founding director of the Pelotonia Institute for Immuno-Oncology. He is a professor of medicine in the Division of Medical Oncology, holds the Klotz Memorial Chair for Cancer Research, and was appointed in 2023 as deputy director for translational research at OSUCCC.
Li's research interests primarily focus on the fields of chaperone biology, immune tolerance, cancer immunology and immunotherapy. He has been continuously funded by the National Institutes of Health (NIH) since 2000, with total funding of over $30 million.
Career
Following his residency and fellowship, Li began his first joint faculty appointment in the Department of Immunology and Medicine at the University of Connecticut School of Medicine (Farmington, CT). In 2010, he was recruited to the Department of Microbiology and Immunology at the Medical University of South Carolina (MUSC), where he served as chair from 2010-2019. During his tenure as chair, the department doubled its NIH funding and increased its national NIH ranking from 79 to 31. Li was also appointed the leader of the Cancer Immunology Program at MUSC's Hollings Cancer Center (2010-2019). Li was inducted into the American Society of Clinical Investigation (2009) and the Association of American Physicians (2018) and is an elected fellow of the American Association for the Advancement of Science (2021) for his work in the interface of chaperone biology and cancer immunology. Recognizing his history of mentorship, he was awarded the Peggy Schachte Research Mentor Award in 2016 from MUSC. In 2022, he received the Mount Sinai Alumni Award for Achievement in Graduate Education.
Contributions to science
Chaperone biology and immune regulation
Li has made groundbreaking discoveries studying the immune chaperone gp96 (also called GRP94), an endoplasmic reticulum-resident protein chaperon belonging to the HSP90 family of heat shock proteins. His research revealed that gp96 is pivotal in various physiological processes, including organ development, innate immunity, and immune tolerance. In cancer, gp96 expression is not only abundant but also further upregulated, driving oncogenesis through its growing client network.
Background: In the 1950s, Prehn, Main, Klein, Old, and others demonstrated the existence of protective immunity against cancer in mice using syngeneic tumor models. This was followed by decades of effort to identify tumor rejection antigens. Pramod Srivastava and Lloyd J. Old isolated a ubiquitous conserved protein, gp96, as a tumor rejection antigen from several chemically induced fibrosarcoma models.
Major contribution to gp96/GRP94 biology: Li defined the ATPase activity of gp96/GRP94, its client network, its structure-function relationship, and the co-chaperone CNPY3. Furthermore, he established its roles in immunity, hematopoiesis, and cancer. gp96/GRP94 was identified as a major luminal protein of the endoplasmic reticulum in multicellular organisms (not in yeast), inducible by metabolic stress. However, there were no previous publications regarding the function of gp96/GRP94 when Li began to study this molecule in the 1990s. It remained unclear how this unmutated protein could trigger an immune response in animals against the tumor from which it originated. Through a biochemical approach, Li was the first to demonstrate that gp96/GRP94 is a bona fide member of the HSP90 family, exhibiting ATP binding, intrinsic ATPase activity, and peptide chaperoning functions. The ability of gp96/GRP94 to form complexes with peptides provided a mechanistic explanation for its antigenicity: it is the chaperoned peptides, rather than gp96/GRP94 itself, that elicit immunogenicity.
However, the physiological role of gp96/GRP94 remained unclear at the time, partly because gp96/GRP94 is absent in yeast, a common genetic model used to study eukaryotic HSPs. Li was the first to use mammalian genetics to uncover the function of GRP94 at the organismal level. He discovered that GRP94 is a major chaperone for integrins,Toll-like receptors (TLRs), Wnt co-receptors LRP5/6, the platelet receptor for the von Willebrand factor, and the latent TGFβ docking receptor GARP (see illustration). gp96/GRP94 thus masterminds three major signals that regulate T cell immunity: antigens, TLRs, and TGFβ.
Li also discovered that co-chaperones regulate gp96/GRP94 substrate specificity. For example, gp96/GRP94 folding of TLRs, LRP5/6, and integrins depends on co-chaperones CNPY3, MesD, and GRP78, respectively. Li’s work advanced our understanding of the role of gp96/GRP94 as a key proteostatic switch for controlling innate immunity, immune tolerance, platelet function, and hematopoiesis. Conceptually, it catalyzes the revelation that ancient chaperones have gained specialized function in mammals, opening a new field of developing chaperone-based therapeutics for a variety of diseases. Li coined the term “immune chaperone” to describe this family of molecules.
Other contributions
Li has also made a significant contribution to understanding sex as a biological variable in immune responses. He discovered the T cell-intrinsic roles of androgen receptors in conferring CD8+ T cell exhaustion in cancer. In addition, he contributed to the first report that loss of the Y chromosome in tumor cells causes T cell dysfunction and increased sensitivity to anti-PD-1 immunotherapy. Li's work has been fundamental in establishing the immunological basis of sex bias in cancer.
Li's other contributions to the field of medicine and biology include the discovery of a molecular key from platelets (via GARP) for cancer immune evasion and the first demonstration of CNPY2 as a critical sensor for PERK-mediated unfolded protein response.
References
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- "Education | Zihai Li". LinkedIn. Retrieved 2024-03-14.
- "Matthew Ringel, Electra Paskett, Zihai Li named deputy directors at OSUCCC". The Cancer Letter. 2023-12-15. Retrieved 2024-02-05.
- "Search results". National Institutes of Health RePORTER. Retrieved 2024-02-05.
- "Zihai Li, MD, PhD". American Society for Clinical Investigation. Retrieved 2024-02-05.
- "22 AAI Members Named AAAS Fellows". The American Association of Immunologists.
- "Spinal cord injury researcher inspires at faculty convocation". web.musc.edu. Retrieved 2024-02-05.
- "HCC FACULTY RECOGNIZED at 2016 CONVOCATION" (PDF). MUSC Hollings Cancer Center. p. 8.
- "2022 Alumni Reunion and Awards Ceremony". Icahn School of Medicine at Mount Sinai. Retrieved 2024-02-05.
- ^ Yang, Yi; Liu, Bei; Dai, Jie; Srivastava, Pramod K.; Zammit, David J.; Lefrançois, Leo; Li, Zihai (February 2007). "Heat Shock Protein gp96 Is a Master Chaperone for Toll-like Receptors and Is Important in the Innate Function of Macrophages". Immunity. 26 (2): 215–226. doi:10.1016/j.immuni.2006.12.005. ISSN 1074-7613. PMC 2847270. PMID 17275357.
- ^ Zhang, Yongliang; Wu, Bill X.; Metelli, Alessandra; Thaxton, Jessica E.; Hong, Feng; Rachidi, Saleh; Ansa-Addo, Ephraim; Sun, Shaoli; Vasu, Chenthamarakshan; Yang, Yi; Liu, Bei; Li, Zihai (2015-02-02). "GP96 is a GARP chaperone and controls regulatory T cell functions". The Journal of Clinical Investigation. 125 (2): 859–869. doi:10.1172/JCI79014. ISSN 0021-9738. PMC 4319419. PMID 25607841.
- ^ Liu, Bei; Yang, Yi; Qiu, Zhijuan; Staron, Matthew; Hong, Feng; Li, Yi; Wu, Shuang; Li, Yunfeng; Hao, Bing; Bona, Robert; Han, David; Li, Zihai (2010-09-21). "Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone". Nature Communications. 1 (1): 79. Bibcode:2010NatCo...1...79L. doi:10.1038/ncomms1070. ISSN 2041-1723. PMC 2982182. PMID 20865800.
- Hua, Yunpeng; White-Gilbertson, Shai; Kellner, Joshua; Rachidi, Saleh; Usmani, Saad Z.; Chiosis, Gabriela; DePinho, Ronald; Li, Zihai; Liu, Bei (2013-11-14). "Molecular Chaperone gp96 Is a Novel Therapeutic Target of Multiple Myeloma". Clinical Cancer Research. 19 (22): 6242–6251. doi:10.1158/1078-0432.ccr-13-2083. ISSN 1078-0432. PMC 3851294. PMID 24077352.
- Rachidi, Saleh; Sun, Shaoli; Wu, Bill X.; Jones, Elizabeth; Drake, Richard R.; Ogretmen, Besim; Cowart, L. Ashley; Clarke, Christopher J.; Hannun, Yusuf A.; Chiosis, Gabriela; Liu, Bei; Li, Zihai (April 2015). "Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis". Journal of Hepatology. 62 (4): 879–888. doi:10.1016/j.jhep.2014.11.010. ISSN 0168-8278. PMC 4369194. PMID 25463537.
- Rachidi, Saleh; Sun, Shaoli; Li, Zihai (May 2015). "Endoplasmic reticulum heat shock protein gp96/grp94 is a pro-oncogenic chaperone, not a tumor suppressor". Hepatology. 61 (5): 1766–1767. doi:10.1002/hep.27400. ISSN 0270-9139. PMC 4939405. PMID 25163410.
- Prehn RT, Main JM. Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 1957;18:769–78.
- Klein G, Sjogren HO, Klein E, Hellstrom KE. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 1960;20:1561–72.
- Old, Lloyd J.; Boyse, Edward A.; Clarke, Donald A.; Carswell, Elizabeth A. (November 1962). "ANTIGENIC PROPERTIES OF CHEMICALLY INDUCED TUMORS*". Annals of the New York Academy of Sciences. 101 (1): 80–106. Bibcode:1962NYASA.101...80O. doi:10.1111/j.1749-6632.1962.tb26446.x. ISSN 0077-8923. S2CID 83847949.
- Srivastava, P K; DeLeo, A B; Old, L J (May 1986). "Tumor rejection antigens of chemically induced sarcomas of inbred mice". Proceedings of the National Academy of Sciences. 83 (10): 3407–3411. Bibcode:1986PNAS...83.3407S. doi:10.1073/pnas.83.10.3407. ISSN 0027-8424. PMC 323523. PMID 3458189.
- ^ Li, Z.; Srivastava, P.K. (August 1993). "Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation". The EMBO Journal. 12 (8): 3143–3151. doi:10.1002/j.1460-2075.1993.tb05983.x. PMC 413580. PMID 8344253.
- Patel, Hardik J.; Patel, Pallav D.; Ochiana, Stefan O.; Yan, Pengrong; Sun, Weilin; Patel, Maulik R.; Shah, Smit K.; Tramentozzi, Elisa; Brooks, James; Bolaender, Alexander; Shrestha, Liza; Stephani, Ralph; Finotti, Paola; Leifer, Cynthia; Li, Zihai (2015-05-14). "Structure–Activity Relationship in a Purine-Scaffold Compound Series with Selectivity for the Endoplasmic Reticulum Hsp90 Paralog Grp94". Journal of Medicinal Chemistry. 58 (9): 3922–3943. doi:10.1021/acs.jmedchem.5b00197. ISSN 0022-2623. PMC 4518544. PMID 25901531.
- Wu, Bill X.; Hong, Feng; Zhang, Yongliang; Ansa-Addo, Ephraim; Li, Zihai (2016-01-01), Isaacs, Jennifer; Whitesell, Luke (eds.), "Chapter Seven - GRP94/gp96 in Cancer: Biology, Structure, Immunology, and Drug Development", Advances in Cancer Research, Hsp90 in Cancer: Beyond the Usual Suspects, 129, Academic Press: 165–190, doi:10.1016/bs.acr.2015.09.001, PMID 26916005
- Lee AS, Bell J, Ting J. Biochemical characterization of the 94- and 78-kilodalton glucose-regulated proteins in hamster fibroblasts. J Biol Chem 1984;259:4616–21.
- Chen, Bin; Zhong, Daibin; Monteiro, Antónia (2006-06-17). "Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms". BMC Genomics. 7 (1): 156. doi:10.1186/1471-2164-7-156. ISSN 1471-2164. PMC 1525184. PMID 16780600.
- Liu, Bei; Dai, Jie; Zheng, Hong; Stoilova, Diliana; Sun, Shaoli; Li, Zihai (2003-12-23). "Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases". Proceedings of the National Academy of Sciences. 100 (26): 15824–15829. Bibcode:2003PNAS..10015824L. doi:10.1073/pnas.2635458100. ISSN 0027-8424. PMC 307652. PMID 14668429.
- ^ Liu, Bei; Li, Zihai (2008-08-15). "Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin". Blood. 112 (4): 1223–1230. doi:10.1182/blood-2008-03-143107. ISSN 0006-4971. PMC 2515121. PMID 18509083.
- Liu, Bei; Yang, Yi; Dai, Jie; Medzhitov, Ruslan; Freudenberg, Marina A.; Zhang, Ping L.; Li, Zihai (2006-11-15). "TLR4 Up-Regulation at Protein or Gene Level Is Pathogenic for Lupus-Like Autoimmune Disease". The Journal of Immunology. 177 (10): 6880–6888. doi:10.4049/jimmunol.177.10.6880. ISSN 0022-1767. PMID 17082602.
- ^ Liu, Bei; Staron, Matthew; Hong, Feng; Wu, Bill X.; Sun, Shaoli; Morales, Crystal; Crosson, Craig E.; Tomlinson, Stephen; Kim, Ingyu; Wu, Dianqing; Li, Zihai (2013-04-23). "Essential roles of grp94 in gut homeostasis via chaperoning canonical Wnt pathway". Proceedings of the National Academy of Sciences. 110 (17): 6877–6882. Bibcode:2013PNAS..110.6877L. doi:10.1073/pnas.1302933110. ISSN 0027-8424. PMC 3637754. PMID 23572575.
- Staron, Matthew; Wu, Shuang; Hong, Feng; Stojanovic, Aleksandra; Du, Xiaoping; Bona, Robert; Liu, Bei; Li, Zihai (2011-06-30). "Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex". Blood. 117 (26): 7136–7144. doi:10.1182/blood-2011-01-330464. ISSN 0006-4971. PMC 3143555. PMID 21576699.
- Kwon, Hyunwoo; Schafer, Johanna M.; Song, No-Joon; Kaneko, Satoshi; Li, Anqi; Xiao, Tong; Ma, Anjun; Allen, Carter; Das, Komal; Zhou, Lei; Riesenberg, Brian; Chang, Yuzhou; Weltge, Payton; Velegraki, Maria; Oh, David Y. (2022-07-29). "Androgen conspires with the CD8 + T cell exhaustion program and contributes to sex bias in cancer". Science Immunology. 7 (73): eabq2630. doi:10.1126/sciimmunol.abq2630. ISSN 2470-9468. PMC 9374385. PMID 35420889.
- Abdel-Hafiz, Hany A.; Schafer, Johanna M.; Chen, Xingyu; Xiao, Tong; Gauntner, Timothy D.; Li, Zihai; Theodorescu, Dan (July 2023). "Y chromosome loss in cancer drives growth by evasion of adaptive immunity". Nature. 619 (7970): 624–631. Bibcode:2023Natur.619..624A. doi:10.1038/s41586-023-06234-x. ISSN 1476-4687. PMC 10975863. PMID 37344596. S2CID 259223163.
- Rachidi, Saleh; Metelli, Alessandra; Riesenberg, Brian; Wu, Bill X.; Nelson, Michelle H.; Wallace, Caroline; Paulos, Chrystal M.; Rubinstein, Mark P.; Garrett-Mayer, Elizabeth; Hennig, Mirko; Bearden, Daniel W.; Yang, Yi; Liu, Bei; Li, Zihai (2017-05-05). "Platelets subvert T cell immunity against cancer via GARP-TGFβ axis". Science Immunology. 2 (11). doi:10.1126/sciimmunol.aai7911. ISSN 2470-9468. PMC 5539882. PMID 28763790.
- Metelli, Alessandra; Wu, Bill X.; Riesenberg, Brian; Guglietta, Silvia; Huck, John D.; Mills, Catherine; Li, Anqi; Rachidi, Saleh; Krieg, Carsten; Rubinstein, Mark P.; Gewirth, Daniel T.; Sun, Shaoli; Lilly, Michael B.; Wahlquist, Amy H.; Carbone, David P. (2020-01-08). "Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β". Science Translational Medicine. 12 (525). doi:10.1126/scitranslmed.aay4860. ISSN 1946-6234. PMC 7814995. PMID 31915300.
- Hong, Feng; Liu, Bei; Wu, Bill X.; Morreall, Jordan; Roth, Brady; Davies, Christopher; Sun, Shaoli; Diehl, J. Alan; Li, Zihai (October 2017). "CNPY2 is a key initiator of the PERK–CHOP pathway of the unfolded protein response". Nature Structural & Molecular Biology. 24 (10): 834–839. doi:10.1038/nsmb.3458. ISSN 1545-9985. PMC 6102046. PMID 28869608.
- American oncologists
- American immunologists
- Ohio State University faculty
- Cancer researchers
- People from Zhengzhou
- 1964 births
- Living people
- Zhengzhou University alumni
- Peking Union Medical College alumni
- Icahn School of Medicine at Mount Sinai alumni
- Albert Einstein College of Medicine alumni
- University of Washington School of Medicine alumni