Zihai Li

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.

Chaperone biology and immune regulation
Li has made seminal discoveries studying the immune chaperone gp96 (also called GRP94), a heat shock protein (HSP90)-related, endoplasmic reticulum-resident protein chaperone. His work uncovered that gp96 plays a key role in many physiologic processes, including organ development, innate immunity, and immune tolerance. In cancer, its abundant expression is further upregulated, and it promotes oncogenesis through its ever-expanding 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 found to be a major luminal protein of the endoplasmic reticulum in multicellular organisms (not in yeast), and is induced 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 was unclear how this unmutated protein could cause animals to generate immunity against a tumor from which it derived. Using a biochemical approach, Li showed for the first time that gp96/GRP94 is a bona fide chaperone of the HSP90 family in that it binds to ATP, processes intrinsic ATPase activity, and chaperones peptides. The ability of gp96/GRP94 to complex with peptides offered a mechanistic explanation for this antigenicity: the chaperoned peptides – not gp96/GRP94 per se – are what produced immunogenicity.

However, at the time, the physiologic role of gp96/GRP94 remained unclear, in part because the gp96/GRP94 is not present in yeast genetic tools 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 determined that co-chaperones regulate gp96/GRP94 substrate specificity. For instance, 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. He coined the term “immune chaperone” to describe this family of molecules.

Other contributions
Li has also made a significant impact on 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.