Central memory phenotype drives success of checkpoint inhibition in combination with CAR T cells
| Autor: | Solin Ali, Anton G. Henssen, Laura Grunewald, Anika Klaus, Johannes H. Schulte, Kathy Astrahantseff, Karin Toews, Angelika Eggert, Sebastian Ochsenreither, Silke Schwiebert, Annika Winkler, Dimitrios L. Wagner, Annette Künkele, Felix Zirngibl, Hedwig E. Deubzer |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
PD-L1 Cancer Research T cell T-Lymphocytes Cell Programmed Cell Death 1 Receptor Receptors Antigen T-Cell Biology B7-H1 Antigen 03 medical and health sciences Neuroblastoma 0302 clinical medicine Cell Line Tumor PD-1 medicine Tumor Microenvironment Humans Molecular Biology Cell sorting chimeric antigen receptor T cell therapy central memory T cells microenvironment Chimeric antigen receptor 030104 developmental biology medicine.anatomical_structure Phenotype 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Chimeric Antigen Receptor T-Cell Therapy Nivolumab human activities 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit |
| Popis: | The immunosuppressive microenvironment in solid tumors is thought to form a barrier to the entry and efficacy of cell-based therapies such as chimeric antigen receptor (CAR) T cells. Combining CAR T cell therapy with checkpoint inhibitors has been demonstrated to oppose immune escape mechanisms in solid tumors and augment antitumor efficacy. We evaluated PD-1/PD-L1 signaling capacity and the impact of an inhibitor of this checkpoint axis in an in vitro system for cancer cell challenge, the coculture of L1CAM-specific CAR T cells with neuroblastoma cell lines. Fluorescence-activated cell sorting-based analyses and luciferase reporter assays were used to assess PD-1/PD-L1 expression on CAR T and tumor cells as well as CAR T cell ability to kill neuroblastoma cells. Coculturing neuroblastoma cell lines with L1CAM-CAR T cells upregulated PD-L1 expression on neuroblastoma cells, confirming adaptive immune resistance. Exposure to neuroblastoma cells also upregulated the expression of the PD-1/PD-L1 axis in CAR T cells. The checkpoint inhibitor, nivolumab, enhanced L1CAM-CAR T cell-directed killing. However, nivolumab-enhanced L1CAM-CAR T cell killing did not strictly correlate with PD-L1 expression on neuroblastoma cells. In fact, checkpoint inhibitor success relied on strong PD-1/PD-L1 axis expression in the CAR T cells, which in turn depended on costimulatory domains within the CAR construct, and more importantly, on the subset of T cells selected for CAR T cell generation. Thus, T cell subset selection for CAR T cell generation and CAR T cell prescreening for PD-1/PD-L1 expression could help determine when combination therapy with checkpoint inhibitors could improve treatment efficacy. |
| Databáze: | OpenAIRE |
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