Tet2 inactivation enhances the anti-tumor activity of tumor-infiltrating lymphocytes
Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating anti-tumor 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 m...
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| Published in | Cancer research (Chicago, Ill.) Vol. 81; no. 8; pp. 1965 - 1976 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
15.02.2021
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| Online Access | Get full text |
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| Abstract | Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating anti-tumor 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 anti-tumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq 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 anti-tumor immunity to suppress tumor growth. |
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| AbstractList | Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating anti-tumor 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 anti-tumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq 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 anti-tumor immunity to suppress tumor growth. |
| Author | Fang, Shaohai Sun, Deqiang Zhang, Joanna Vo, Anh Tran Tram Martinez-Moczygemba, Margarita Lee, Minjung Li, Jianfang Han, Wei Li, Jia Zeng, Hongxiang Isgandarova, Sevinj Huang, Yun Zhou, Yubin |
| AuthorAffiliation | 6. Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA 7. The CPRIT scholar for cancer research 2. College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA 3. Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA 4. Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA 1. Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA 5. Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA |
| AuthorAffiliation_xml | – name: 6. Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA – name: 2. College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA – name: 7. The CPRIT scholar for cancer research – name: 3. Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA – name: 1. Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA – name: 4. Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA – name: 5. Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA |
| Author_xml | – sequence: 1 givenname: Minjung surname: Lee fullname: Lee, Minjung organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 2 givenname: Jianfang surname: Li fullname: Li, Jianfang organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 3 givenname: Jia surname: Li fullname: Li, Jia organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 4 givenname: Shaohai surname: Fang fullname: Fang, Shaohai organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 5 givenname: Joanna surname: Zhang fullname: Zhang, Joanna organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 6 givenname: Anh Tran Tram surname: Vo fullname: Vo, Anh Tran Tram organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 7 givenname: Wei surname: Han fullname: Han, Wei organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 8 givenname: Hongxiang surname: Zeng fullname: Zeng, Hongxiang organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 9 givenname: Sevinj surname: Isgandarova fullname: Isgandarova, Sevinj organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 10 givenname: Margarita surname: Martinez-Moczygemba fullname: Martinez-Moczygemba, Margarita organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 11 givenname: Yubin surname: Zhou fullname: Zhou, Yubin organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 12 givenname: Deqiang surname: Sun fullname: Sun, Deqiang email: dsun@gomicstech.com, yun.huang@tamu.edu organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research – sequence: 13 givenname: Yun surname: Huang fullname: Huang, Yun email: dsun@gomicstech.com, yun.huang@tamu.edu organization: Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI, 48104, USA Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030, USA Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA The CPRIT scholar for cancer research |
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| Notes | These authors contributed equally to this study. YH directed and oversaw the project. ML performed in vitro tissue culture work and in vivo B16-OVA immunotherapy model. ML and SF performed sequencing library preparation. ML, JZ and AV performed in vitro cytotoxic experiments. WH and HZ supported the animal model work. SI and MM supported the flow cytometry analysis. JFL, DS and JL performed sequencing data analysis. YH and YZ wrote the manuscript. All the authors participated in the discussion, data interpretation and manuscript editing discussion. Leading contact: Name: Yun Huang, Mailing address: 2121 W. Holcombe Blvd, Houston, TX 77030 USA, Phone: 713-677-7484 Author contributions |
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| Snippet | Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating anti-tumor immunity during tumor onset and progression. Epigenetic... |
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| Title | Tet2 inactivation enhances the anti-tumor activity of tumor-infiltrating lymphocytes |
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