PD-L1 methylation restricts PD-L1/PD-1 interactions to control cancer immune surveillance

Author:

Huang Changsheng1ORCID,Ren Shengxiang2,Chen Yaqi1ORCID,Liu Anyi1,Wu Qi1,Jiang Tao2ORCID,Lv Panjing3ORCID,Song Da1,Hu Fuqing1,Lan Jingqing1,Sun Li4ORCID,Zheng Xue5,Luo Xuelai1,Chu Qian4ORCID,Jia Keyi2ORCID,Li Yan3ORCID,Wang Jun6,Zou Caicun2,Hu Junbo1,Wang Guihua1ORCID

Affiliation:

1. GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

2. Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.

3. Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

4. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

5. Wuhan Blood Center, Wuhan 430030, China.

6. Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Abstract

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) have enabled some patients with cancer to experience durable, complete treatment responses; however, reliable anti–PD-(L)1 treatment response biomarkers are lacking. Our research found that PD-L1 K162 was methylated by SETD7 and demethylated by LSD2. Furthermore, PD-L1 K162 methylation controlled the PD-1/PD-L1 interaction and obviously enhanced the suppression of T cell activity controlling cancer immune surveillance. We demonstrated that PD-L1 hypermethylation was the key mechanism for anti–PD-L1 therapy resistance, investigated that PD-L1 K162 methylation was a negative predictive marker for anti–PD-1 treatment in patients with non–small cell lung cancer, and showed that the PD-L1 K162 methylation:PD-L1 ratio was a more accurate biomarker for predicting anti–PD-(L)1 therapy sensitivity. These findings provide insights into the regulation of the PD-1/PD-L1 pathway, identify a modification of this critical immune checkpoint, and highlight a predictive biomarker of the response to PD-1/PD-L1 blockade therapy.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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