Liu et al. characterized the human tumor–immune interactions in hepatic portal vein blood and primary and metastatic malignant lesions at single-cell scale, and identified the direct interaction between HLA-E in circulating tumor cells (CTC) and CD94-NKG2A in NK cells that serves as an immune checkpoint. Antibody blockade of the HLA-E/CD94-NKG2A interaction, or knockdown of H2-T23 (muHLA-E) restored NK cell-mediated cytotoxicity and prevented tumor metastasis in vivo. Mechanistically, tumor cells acquired platelet-derived RGS18 and upregulated the expression of HLA-E through the AKT-GSK3b-CREB signaling pathway.
Contributed by Shishir Pant
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.
Author Info: (1) Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovatio
Author Info: (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 Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China
(3) Department of Pancreatic Surgery, West China Hospital, 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
