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Myc inhibition tips the immune balance to promote antitumor immunity

Cellular & Molecular Immunology volume 19, pages 1030–1041 (2022)Cite this article

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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.

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The data that support the findings of this study are available from the corresponding authors upon request.

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Acknowledgements

We thank all members of the Xiao and Liu labs (Xiamen University), Xiao Lei Chen (Xiamen University), Chia-Hao Lin and Li-Fan Lu (UCSD) for discussion and technical assistance. We thank Lixin Hong, Xiaohong Ma, Xiufeng Sun at the Xiamen University Flow Cytometry Core and Suqin Wu in the XMU Laboratory Animal Center for technical assistance. This study was supported by the National Natural Science Foundation of China (31770953, 81830047, 81961138008 to CX, 32070877 to W-HL, and 31570883 to NX), 1000 Young Talents Program of China (NX), and the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720170064 to CX). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. Zhe Huang & Changchun Xiao

    Present address: Sanofi Institute for Biomedical Research, Suzhou, 215123, Jiangsu, China

  2. These authors contributed equally: Chao Yang, Yun Liu, Yudi Hu.

Authors and 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

    Chao Yang, Yun Liu, Jun Xie, Yazhen Hong, Nengming Xiao, Wen-Hsien Liu & Changchun Xiao

  2. Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China

    Yudi Hu & Qiyuan Li

  3. 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

    Liang Fang, Huanhuan Cui & Wei Chen

  4. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Zhe Huang & Changchun Xiao

Authors
  1. Chao Yang
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Contributions

CY, YL and CX conceived the study. CY and YL performed most mouse, cell and molecular biology experiments. CY, YL and LF performed the single-cell sequencing experiment. YH analyzed the single-cell sequencing and RNA sequencing data. HC and JX performed some molecular experiments. YH, WC, NX, QL, W-HL, and CX cosupervised the project. CY, YL, ZH, W-HL, and CX wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Chao Yang, Qiyuan Li, Wen-Hsien Liu or Changchun Xiao.

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The authors declare no competing interests.

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Yang, C., Liu, Y., Hu, Y. et al. Myc inhibition tips the immune balance to promote antitumor immunity. Cell Mol Immunol 19, 1030–1041 (2022). https://doi.org/10.1038/s41423-022-00898-7

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