2. Academic Validation
  3. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance

Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance

  • Cancer Cell. 2023 Feb 13;41(2):272-287.e9. doi: 10.1016/j.ccell.2023.01.001.
Xiaowei Liu 1,  Jinen Song 1,  Hao Zhang 2,  Xinyu Liu 1,  Fengli Zuo 1,  Yunuo Zhao 3,  Yujie Zhao 1,  Xiaomeng Yin 3,  Xinyu Guo 1,  Xi Wu 1,  Hu Zhang 1,  Jie Xu 4,  Jianping Hu 5,  Jing Jing 1,  Xuelei Ma 6,  Hubing Shi 7
Affiliations

Affiliations

  • 1 Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China.
  • 2 Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 4 Institutes of Biological Sciences, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China.
  • 5 College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, Sichuan 610106, China.
  • 6 Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: [email protected].
  • 7 Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China. Electronic address: [email protected].
PMID: 36706761 DOI: 10.1016/j.ccell.2023.01.001
Abstract

Circulating tumor cells (CTCs), shed by primary malignancies, function as "seeds" for distant metastasis. However, it is still largely unknown how CTCs escape immune surveillance. Here, we characterize the transcriptomes of human pancreatic ductal adenocarcinoma CTCs, primary, and metastatic lesions at single-cell scale. Cell-interaction analysis and functional studies in vitro and in vivo reveal that CTCs and natural killer (NK) cells interact via the immune checkpoint molecule pair HLA-E:CD94-NKG2A. Disruption of this interaction by blockade of NKG2A or knockdown of HLA-E expression enhances NK-mediated tumor cell killing in vitro and prevents tumor metastasis in vivo. Mechanistic studies indicate that platelet-derived RGS18 promotes the expression of HLA-E through AKT-GSK3β-CREB signaling, and overexpression of RGS18 facilitates pancreatic tumor hepatic metastasis. In conclusion, platelet-derived RGS18 protects CTCs from NK-mediated immune surveillance by engaging the immune checkpoint HLA-E:CD94-NKG2A. Interruption of the suppressive signaling prevents tumor metastasis in vivo by immune elimination of CTCs.

Keywords

NK cells; circulating tumor cells; immune checkpoint; liver metastasis; pancreatic ductal adenocarcinoma; platelet; single-cell RNA sequencing.

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