Soluble programmed death ligand‐1‐induced immunosuppressive effects on chimeric antigen receptor‐natural killer cells targeting Glypican‐3 in hepatocellular carcinoma

• Published in: Immunology Vol. 169; no. 2; pp. 204 - 218
• Main Authors: Chen, Lin, Liu, Siyuan, Adah, Dickson, Sun, Qingyang, Liang, Zhaoduan, Ho, Mitchell, Sun, Beicheng
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.06.2023
• Subjects: Affinity; Antibodies; Antigens; Apoptosis; Carcinoma, Hepatocellular; CAR‐NK cells; Chimeric antigen receptors; Clinical trials; Glypicans - genetics; Heparan sulfate proteoglycans; Hepatocellular carcinoma; Humans; Immunosuppression; Immunotherapy; Killer Cells, Natural; Ligands; Liver cancer; Liver Neoplasms; Lymphocytes; Lymphocytes T; Natural killer cells; PD‐1; Receptors; Receptors, Chimeric Antigen - genetics; Solid tumors; sPD‐L1; Tumor Microenvironment; Tumors; tumour microenvironment; tumour microenvironment; CAR-NK cells; PD-1; sPD-L1
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13624

Although the pre‐clinical study of chimeric antigen receptor (CAR)‐natural killer (NK) cell was effective against various tumours, immunosuppression mediated by tumour microenvironment hampers their application and several efforts have been explored to improve their effect in combating solid tumours. Glypican 3 (GPC3) is a promising target for hepatocellular carcinoma (HCC), and CAR‐T cells targeting GPC3 have been tested in clinical trials. Based on an affinity‐enhanced antibody (hYP7) targeting GPC3, we constructed GPC3‐CAR‐NK cells to explore their potential function in the treatment of HCC. We found that patients with HCC secreted high levels of soluble programmed death‐ligand 1 (sPD‐L1), which inhibits the function of CAR‐NK cells targeting GPC3. In addition, we combined high‐affinity sPD‐L1 variant (L3C7c‐Fc) with GPC3‐CAR‐NK cells to solve the problem of GPC3‐CAR‐NK inhibition. Our studies demonstrated that L3C7c‐Fc could enhance the therapeutic effect of CAR‐NK cells by reversing the suppression of sPD‐L1, which provides the experimental evidence for the subsequent development of HCC immunotherapy strategies. Programmed cell death protein 1 (PD‐1) is expressed on chimeric antigen receptor (CAR)‐natural killer (NK) cells, on the other hand, soluble programmed death‐ligand 1 (sPD‐L1) level and membrane PD‐L1 (mPD‐L1) expression are enhanced in hepatocellular carcinoma (HCC) patients. The ligation of PD‐1 with sPD‐L1 or mPD‐L1 inhibited the function of CAR‐NK cells. L3C7c‐Fc‐blocked PD‐1 axis and rescues CAR‐NK cells function, which is beneficial to HCC patients.