TY - JOUR T1 - First immunotherapeutic CAR-T cells against the immune checkpoint protein HLA-G JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2020-001998 VL - 9 IS - 3 SP - e001998 AU - François Anna AU - Elodie Bole-Richard AU - Joel LeMaoult AU - Marie Escande AU - Martin Lecomte AU - Jean-Marie Certoux AU - Philippe Souque AU - Francine Garnache AU - Olivier Adotevi AU - Pierre Langlade-Demoyen AU - Maria Loustau AU - Julien Caumartin Y1 - 2021/03/01 UR - http://jitc.bmj.com/content/9/3/e001998.abstract N2 - 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. ER -