Tet2 inactivation enhances the anti-tumor activity of tumor-infiltrating lymphocytes

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 8; pp. 1965 - 1976
• Main Authors: Lee, Minjung, Li, Jianfang, Li, Jia, Fang, Shaohai, Zhang, Joanna, Vo, Anh Tran Tram, Han, Wei, Zeng, Hongxiang, Isgandarova, Sevinj, Martinez-Moczygemba, Margarita, Zhou, Yubin, Sun, Deqiang, Huang, Yun
• Format: Journal Article
• Language: English
• Published: 15.02.2021
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-20-3213

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.