Tet2 Inactivation Enhances the Anti-Tumor Activity of Tumor-Infiltrating Lymphocytes (TILs) to Curtail Melanoma Growth

Minjung Lee,Jianfang Li,Shaohai Fang,Joanna Zhang,Anh Tran Tram Vo,Wei Han,Hongxiang Zeng,Sevinj Isgandarova,Margarita Martinez Moczygemba,Yubin Zhou,Jia Li,Deqiang Sun,Yun Huang

doi:10.1182/blood-2020-137242

Abstract

Inactivation of tumor infiltrating lymphocytes (TILs) 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 the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further revealed that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs, and that Tet2 inactivation could benefit anti-tumor immunity to boost tumor suppression. Disclosures No relevant conflicts of interest to declare.

Highlights

Dynamic epigenetic alteration has been observed in CD8+ tumor infiltrating lymphocytes (TILs) during tumor progression [1, 2]
We focused on the chromatin accessibility states of the BATF binding regions in both WT and Tet2KO TILs (Figure 5C)
TET2 mutations are often observed in elderly individuals with clonal hematopoiesis (CH) [16], suggesting that TET2 mutations are present in the progeny of hematopoietic stem and progenitor cells (HSCPs), such as monocytes and lymphocytes, and subsequently alters their functions during innate and adaptive immune response

Summary

Introduction

Dynamic epigenetic alteration has been observed in CD8+ tumor infiltrating lymphocytes (TILs) during tumor progression [1, 2]. Epigenetic plasticity is one of the critical factors governing the expression of key genes involved in defining the status of TILs during tumor development. Recent studies have shown that DNA methylation plays an essential role in regulating CD8+ T cell immune response during chronic infection and tumorigenesis [3,4,5,6]. Both effector and inhibitory genes are tightly controlled by DNA methylation during CD8+ expansion, activation and exhaustion [7]. DNA methylation-associated epigenetic reprogramming is critical for the adaptive immune response of CD8+ T cells

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Conclusion