2. Academic Validation
  3. Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

  • Cancer Res. 2021 Apr 15;81(8):1965-1976. doi: 10.1158/0008-5472.CAN-20-3213.
Minjung Lee  # 1,  Jianfang Li  # 1,  Jia Li 1,  Shaohai Fang 1,  Joanna Zhang 1 2,  Anh Tran Tram Vo 1 3,  Wei Han 1,  Hongxiang Zeng 1,  Sevinj Isgandarova 4,  Margarita Martinez-Moczygemba 4 5 6,  Yubin Zhou 5 7,  Deqiang Sun 8 5 6,  Yun Huang 8 5 6
Affiliations

Affiliations

  • 1 Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
  • 2 College of Literature, Science and the Arts, University of Michigan, Ann Arbor, Michigan.
  • 3 Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
  • 4 Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
  • 5 Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, Texas.
  • 6 The CPRIT Scholar for Cancer Research.
  • 7 Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
  • 8 Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas. yun.huang@tamu.edu dsun@gomicstech.com.
  • # Contributed equally.
PMID: 33589517 DOI: 10.1158/0008-5472.CAN-20-3213
Abstract

Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that TET2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that TET2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8+ T-cell activation. Furthermore, the ETS family of transcription factors contributed to augmented CD8+ T-cell function following TET2 depletion. Overall, our study establishes that TET2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that TET2 inactivation could promote antitumor immunity to suppress tumor growth. SIGNIFICANCE: This study suggests that ablation of TET2+ from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.

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