First immunotherapeutic CAR-T cells against the immune checkpoint protein HLA-G. Issue 3 (18th March 2021)

• Record Type: Journal Article
• Authors: Anna, François; Bole-Richard, Elodie; LeMaoult, Joel; Escande, Marie; Lecomte, Martin; Certoux, Jean-Marie; Souque, Philippe; Garnache, Francine; Adotevi, Olivier; Langlade-Demoyen, Pierre; Loustau, Maria; Caumartin, Julien
• Is Part Of: Journal for immunotherapy of cancer. Volume 9:Issue 3(2021)
• Publication Date: 2021-03-18
• Subjects: immunotherapy -- adoptive -- tumor escape -- receptors -- chimeric antigen -- antigens -- tumor-associated -- carbohydrate -- biomarkers -- tumor; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-001998
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: CAR-T cells immunotherapy is a breakthrough in the treatment of hematological malignancies such as acute lymphoblastic leukemia (ALL) and B-cell malignancies. However, CAR-T therapies face major hurdles such as the lack of tumor-specific antigen (TSA), and immunosuppressive tumor microenvironment sometimes caused by the tumorous expression of immune checkpoints (ICPs) such as HLA-G. Indeed, HLA-G is remarkable because it is both a potent ICP and a TSA. HLA-G tumor expression causes immune escape by impairing innate and adaptive immune responses and by inducing a suppressive microenvironment. Yet, to date, no immunotherapy targets it. Methods: We have developed two anti-HLA-G third-generation CARs based on new anti-HLA-G monoclonal antibodies. Results: Anti-HLA-G CAR-T cells were specific for immunosuppressive HLA-G isoforms. HLA-G-activated CAR-T cells polarized toward T helper 1, and became cytotoxic against HLA-G + tumor cells. In vivo, anti-HLA-G CAR-T cells were able to control and eliminate HLA-G + tumor cells. The interaction of tumor-HLA-G with interleukin (IL)T2-expressing T cells is known to result in effector T cell functional inhibition, but anti-HLA-G CAR-T cells were insensitive to this inhibition and still exerted their function even when expressing ILT2. Lastly, we show that anti-HLA-G CAR-T cells differentiated into long-term memory effector cells, and seemed not to lose function even after repeated stimulation by HLA-G-expressing tumor cells. Conclusion: We report for the first time that HLA-G, which is both a TSA and an ICP, constitutes a valid target for CAR-T cell therapy to specifically target and eliminate both tumor cells and HLA-G + suppressive cells.