Feb 2023
Abstract:
In this
presentation I will discuss the discovery of the first histone
demethylase LSD1 and our more recent work investigating epigenetic
regulation in immuno-oncology. I will discuss our efforts towards
understanding how epigenetic regulation impacts cancer and immune cell
behaviors, enabling poorly immunogenic tumors to respond to immune
checkpoint blockade (ICB) therapy and to promote a durable tumor
response to ICB therapy, which are two major questions in the field.
Bio:
Yang
Shi received his PhD from New York University where he studied
regulation of a multi-gene family in mice. He carried out postdoctoral
research in the lab of Dr. Thomas Shenk at Princeton University where he
discovered the transcription factor YY1 (Yin Yang 1 for its ability to
both activate and repress transcription), which plays a critical role in
many important biological processes.
Yang
Shi began his independent research career at Harvard Medical School as a
tenure track assistant professor and received tenure and full
professorship in the Department of Pathology at Harvard Medical School
in 2004. In 2009 he joined the Newborn Medicine Division of Boston
Children's Hospital and held a Merton Bernfield Professorship. He became
the inaugural C. H. Waddington Professor of Pediatrics of Harvard
Medical School in 2018.
Yang
Shi joined the Ludwig Institute for Cancer Research, Oxford University
in 2020. His honors include Ray Wu Prize (2009), election to the
American Association for the Advancement of Science (2011), American
Cancer Society Research Professor (2012), election to the American
Academy of Arts and Sciences (2016), the National Cancer Institute
Outstanding Investigator Award (2017) and election to the AACR Academy
(2022)
Yang's
most significant and widely known scientific contribution is the
discovery of the first histone demethylase LSD1, which overturned the
40-year-old dogma that histone methylation is irreversible. This
groundbreaking discovery was published in Cell in 2004, and was selected
by Cell as one of the 25 landmark publications over forty-year history
of Cell. His lab is also a major contributor to the discovery of
additional histone demethylases, which belong to the JmjC
domain-containing, dioxygenase family of enzymes.
Subsequent
to the histone demethylase discoveries, work from the Shi lab provided
important insights into the mechanism of action of histone demethylases
and their roles in biological and pathological processes. These
discoveries not only provided critical novel insights into epigenetic
regulation but also revealed new drug targets for cancer therapy, for
instance, small molecules targeting LSD1 are now in phase I and II
clinical trials for AML and myelofibrosis.
Excitingly, Yang's most recent work also uncovered a role for LSD1 in immune checkpoint blockage, i.e., inhibition of LSD1 in tumors can turn "cold" tumor "hot", thus enabling immune checkpoint blockage (ICB) for cancers that otherwise are not responsive to immune therapy. Furthermore, perturbation of LSD1 in T cells results in a sustained response to ICB therapy by antagonizing T cell exhaustion. These findings laid the foundation for future combination therapies involving the use of inhibitors of epigenetic regulators such as LSD1 and checkpoint inhibitors for immune-resistant cancers.