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*, Qiang Yu*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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.

Original languageEnglish
Article number4118
JournalNature Communications
Volume13
Number of pages18
ISSN2041-1723
DOIs
Publication statusPublished - 15. Jul 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Animals
  • Cell Line, Tumor
  • Epigenesis, Genetic
  • Humans
  • Hypoxia/genetics
  • Immunotherapy/methods
  • Mice
  • Triple Negative Breast Neoplasms/genetics
  • Tumor Microenvironment/genetics

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