HDAC inhibition potentiates anti-tumor activity of macrophages and enhances anti-PD-L1-mediated tumor suppression

Xiaolei Li, Xiao Su, Rui Liu, Yongsha Pan, Jiankai Fang, Lijuan Cao, Chao Feng, Qianwen Shang, Yongjing Chen, Changshun Shao, Yufang Shi

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Despite the widespread use of the blockade of immune checkpoints, for a significant number of cancer patients, these therapies have proven ineffective, presumably due to the immunosuppressive nature of the tumor microenvironment (TME). Critical drivers of immune escape in the TME include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which not only mediate immune suppression, but also facilitate metastatic dissemination and impart resistance to immunotherapies. Thus, strategies that convert them into tumor fighters may offer great therapeutic potential. In this study, we evaluated whether pharmacologic modulation of macrophage phenotype by HDAC inhibitors (HDACi) could produce an anti-tumor effect. We demonstrated that low-dose HDACi trichostatin-A (TSA) markedly reshaped the tumor immune microenvironment by modulating the suppressive activity of infiltrating macrophages and inhibiting the recruitment of MDSCs in various tumors. These actions, in turn, augmented anti-tumor immune responses and further enhanced anti-tumor effects of immunotherapies. HDAC inhibition, however, also upregulated PD-L1, thereby limiting the beneficial therapeutic effects. Indeed, combining low-dose TSA with anti-PD-L1 in this model significantly enhanced the durability of tumor reduction and prolonged survival of tumor-bearing mice, compared with the effect of either treatment alone. These data introduce HDAC inhibition as a potential means to harness the anti-tumor potential of macrophages in cancer therapy.

Original languageEnglish (US)
Pages (from-to)1836-1850
Number of pages15
JournalOncogene
Volume40
Issue number10
DOIs
StatePublished - Mar 10 2021

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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