Modulation of SRSF2 expression reverses the exhaustion of TILs via the epigenetic regulation of immune checkpoint molecules

Ziqiang Wang,Wei Chen,Weiming Wang,Weiren Huang,Xiaoxia Wang,Zhiming Cai,Wanjun Wu,Yikun Huang,Kun Li

doi:10.1007/s00018-019-03362-4

Abstract

The elevated expression of immune checkpoints by the tumor microenvironment is associated with poor prognosis in several cancers due to the exhaustion of tumor-infiltrating lymphocytes (TILs), and the effective suppression of the expression of these genes is key to reversing the exhaustion of TILs. Herein, we determined that serine/arginine-rich splicing factor 2 (SRSF2) is a target for blocking the tumor microenvironment-associated immunosuppressive effects. We found that the expression of SRSF2 was increased in exhausted T cells and that SRSF2 was involved in multiple immune checkpoint molecules mediating TILs’ exhaustion. Furthermore, SRSF2 was revealed to regulate the transcription of these immune checkpoint genes by associating with an acyl-transferases P300/CBP complex and altering the H3K27Ac level near these genes, thereafter influencing the recruitment of signal transducer and activator of transcription 3 (STAT3) to these gene promoters. Collectively, our data indicated that SRSF2 functions as a modulator of the anti-tumor response of T cells and may be a therapeutic target for reversing the exhaustion of TILs.

Highlights

Renal cell carcinoma (RCC) is the most common type of kidney cancer and accounts for 90–95% of all kidney cancer diagnosis and 3% of adult malignancies [1]
We found that tumor cells isolated from RCC tissue did not trigger the immune response of tumor-infiltrating lymphocytes (TILs) and downregulation of serine/arginine-rich splicing factor 2 (SRSF2) in these TILs could significantly improve their immune response against tumor cells
The results demonstrated that only tumor cell lines isolated from sample 10 could stimulate the production of IFN-γ in TILs (Fig. 1a)

Summary

Introduction

Renal cell carcinoma (RCC) is the most common type of kidney cancer and accounts for 90–95% of all kidney cancer diagnosis and 3% of adult malignancies [1]. It is known that both innate and adaptive immune cells with RCC specificity develop naturally in most patients, and lymphocytes are recruited to the tumor to secrete cytokines [3, 4]. Higher numbers of T cells in RCC tissue correlates with a poorer prognosis as there are limitations on immune cells and the capacity with which they exert their effector functions [5, 6]. This suggests that for some unknown reasons, RCC T cells are unable to produce an immune response against the tumor cells and control tumor growth. Recent studies have suggested that the immunosuppressive effects of the tumor microenvironment may be the cause of this T-cell failure in RCC tissue

Methods

Results

Conclusion