Human leukocyte antigen G as a novel target for switch-based chimeric antigen receptor natural killer cell therapy of solid cancers.

Human leukocyte antigen G (HLA-G) is a molecule within the tumor microenvironment (TME) that modulates the innate and adaptive immune systems by interacting with inhibitory receptors on the surface of immune cells and thus functions as an immune checkpoint. It could be potentially expressed by all tumor types but is not expressed by either healthy tissues surrounding the tumor cells or vital normal tissues. Chimeric antigen receptors (CARs) for adoptive cell therapy (ACT) have been successful in clinical trials against hematologic cancers; however, challenges have been encountered when applying this approach to the treatment of solid tumors. These obstacles are mainly due to the lack of a ubiquitous tumor-associated antigen (TAA) across different tumor types without “on-target/off-tumor” reactivity and the immunosuppressive nonphysical TME. To address these issues, we developed a novel switch HLA-G CAR carrying an inducible Caspase9 (iC9) suicide gene system that binds to HLA-G1~G7 isoforms and expressed this CAR in natural killer (NK) cells. We tested these HLA-G CAR-NK cells in a variety of adult cancer models and discovered that they mediate significant tumor cytolysis in triple-negative breast cancer (TNBC), glioblastoma (GBM), pancreatic (PA) cancer, and ovarian (OV) cancer in vitro and in TNBC and GBM xenograft models in vivo. Coculturing HLA-G CAR-NK cells with vital normal cell lines did not cause cell damage. We further discovered that surface-exposed HLA-G is chemoinducible, which in turn increases tumor sensitivity to both HLA-G CAR effector-mediated antitumor responses and tumor-infiltrative NK cells. The underlying mechanism of tumor and HLA-G CAR NK cell interaction may be through upregulation of membranous HLA-G via demethylation of the TAP-1 promoter or enhanced activity of the TAP1/signal peptide peptidase (SPP) pathways. In conclusion, HLA-G CAR-NK cells could be an option for treating solid tumors of different cell types, and a regimen comprising chemotherapy followed by HLA-G CAR immunotherapy may improve responses compared to those achieved with CAR-T cell immunotherapy alone. Citation Format: Chia-Ing Jan, Shi-Wei Huang, Peter Canoll, Yu-Chuan Lin, Hsin-Man Lu, Shao-Chih Chio, Der-Yang Cho. Human leukocyte antigen G as a novel target for switch-based chimeric antigen receptor natural killer cell therapy of solid cancers [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A61.