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  3. Myc inhibition tips the immune balance to promote antitumor immunity

Myc inhibition tips the immune balance to promote antitumor immunity

  • Cell Mol Immunol. 2022 Sep;19(9):1030-1041. doi: 10.1038/s41423-022-00898-7.
Chao Yang  # 1,  Yun Liu  # 2,  Yudi Hu  # 3,  Liang Fang 4,  Zhe Huang 5 6,  Huanhuan Cui 4,  Jun Xie 2,  Yazhen Hong 2,  Wei Chen 4,  Nengming Xiao 2,  Qiyuan Li 7,  Wen-Hsien Liu 8,  Changchun Xiao 9 10 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, Fujian, China. yangchaoisfine@163.com.
  • 2 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, Fujian, China.
  • 3 Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China.
  • 4 Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, 518005, Guangdong, China.
  • 5 Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • 6 Sanofi Institute for Biomedical Research, Suzhou, 215123, Jiangsu, China.
  • 7 Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China. qiyuan.li@xmu.edu.cn.
  • 8 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, Fujian, China. whliu@xmu.edu.cn.
  • 9 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, Fujian, China. cxiao@scripps.edu.
  • 10 Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA. cxiao@scripps.edu.
  • 11 Sanofi Institute for Biomedical Research, Suzhou, 215123, Jiangsu, China. cxiao@scripps.edu.
  • # Contributed equally.
PMID: 35962189 DOI: 10.1038/s41423-022-00898-7
Abstract

Aberrant expression of Myc is one of the most common oncogenic events in human cancers. Scores of Myc inhibitors are currently under development for treating Myc-driven cancers. In addition to directly targeting tumor cells, Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor regression. However, the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly understood. Here, we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of Myc. Combining genetic and pharmacologic approaches, we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T (Treg) cells and the differentiation of resting Treg (rTreg) cells to activated Treg (aTreg) cells in tumors. Importantly, we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of Myc. Although ablation of the Myc gene has been shown to suppress CD8 T cell function, Treg cells, which express much less Myc protein than CD8 T cells, are more sensitive to Myc inhibitors. The differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc inhibition. Our findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.

Keywords

Antitumor immunity; Cancer immunotherapy; Differential sensitivity; Myc inhibition; Regulatory T cells.

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