Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy

Shijun Ma, Yue Zhao, Wee Chyan Lee, Li-Teng Ong, Puay Leng Lee, Zemin Jiang, Gokce Oguz, Zhitong Niu, Min Liu, Jian Yuan Goh, Wenyu Wang, Matias A. Bustos, Sidse Ehmsen, Adaikalavan Ramasamy, Dave S. B. Hoon, Henrik J. Ditzel, Ern Yu Tan, Qingfeng Chen () and Qiang Yu ()
Additional contact information
Shijun Ma: Agency for Science, Technology and Research (A*STAR)
Yue Zhao: Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research (A*STAR)
Wee Chyan Lee: Agency for Science, Technology and Research (A*STAR)
Li-Teng Ong: Agency for Science, Technology and Research (A*STAR)
Puay Leng Lee: Agency for Science, Technology and Research (A*STAR)
Zemin Jiang: Agency for Science, Technology and Research (A*STAR)
Gokce Oguz: Agency for Science, Technology and Research (A*STAR)
Zhitong Niu: The Sixth Affiliated Hospital of Sun Yat-sen University
Min Liu: Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research (A*STAR)
Jian Yuan Goh: Agency for Science, Technology and Research (A*STAR)
Wenyu Wang: The Sixth Affiliated Hospital of Sun Yat-sen University
Matias A. Bustos: Providence Health System
Sidse Ehmsen: Odense University Hospital
Adaikalavan Ramasamy: Agency for Science, Technology and Research (A*STAR)
Dave S. B. Hoon: Providence Health System
Henrik J. Ditzel: Odense University Hospital
Ern Yu Tan: Tan Tock Seng Hospital
Qingfeng Chen: Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research (A*STAR)
Qiang Yu: Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC.

Date: 2022
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DOI: 10.1038/s41467-022-31764-9

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