Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes
- 15 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (8), 1965-1976
- https://doi.org/10.1158/0008-5472.can-20-3213
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.Other Versions
Funding Information
- CPRIT (CPRIT RP120348, RP170002)
- Cancer Prevention and Research Institute of Texas (RP180131)
- Cancer Prevention and Research Institute of Texas (RP190581)
- NIH (R01HL134780, R21GM138824, R01HL146852)
- NIH (R01GM112003, R21GM132778, R01CA232017)
- Welch Foundation (BE-1913-20190330)
- American Cancer Society (RSG-18-043-01-LIB)
- American Cancer Society (RSG-16-215-01-TBE)
This publication has 41 references indexed in Scilit:
- Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector FunctionThe Journal of Immunology, 2013
- Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesisNature Genetics, 2012
- Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNAScience, 2011
- Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-CarboxylcytosineScience, 2011
- Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in miceProceedings of the National Academy of Sciences of the United States of America, 2011
- TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelityNature, 2011
- Mutation inTET2in Myeloid CancersThe New England Journal of Medicine, 2009
- Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1Science, 2009
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- T cell receptor antagonist peptides induce positive selectionCell, 1994