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

• Published in: Cellular and molecular life sciences : CMLS 2020-09, Vol.77 (17), p.3441-3452
• Main Authors: Wang, Ziqiang, Li, Kun, Chen, Wei, Wang, Xiaoxia, Huang, Yikun, Wang, Weiming, Wu, Wanjun, Cai, Zhiming, Huang, Weiren
• Format: Article
• Language: English
• Subjects: Arginine; Biochemistry; Biomedical and Life Sciences; Biomedicine; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Biology; CTLA-4 Antigen - genetics; CTLA-4 Antigen - metabolism; Epigenesis, Genetic; Exhaustion; Gene expression; Genes; Histones - metabolism; Humans; Immune checkpoint; Interferon-gamma - metabolism; Jurkat Cells; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Life Sciences; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Original; Original Article; p300-CBP Transcription Factors - metabolism; Promoter Regions, Genetic; RNA Interference; RNA, Small Interfering - metabolism; Serine; Serine-Arginine Splicing Factors - antagonists & inhibitors; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Splicing; Splicing factors; Stat3 protein; STAT3 Transcription Factor - metabolism; Transcription; Tumor Microenvironment; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03362-4

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.