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Central memory phenotype drives success of checkpoint inhibition in combination with CAR T cells
Author(s) -
Toews Karin,
Grunewald Laura,
Schwiebert Silke,
Klaus Anika,
Winkler Annika,
Ali Solin,
Zirngibl Felix,
Astrahantseff Kathy,
Wagner Dimitrios L.,
Henssen Anton G.,
Deubzer Hedwig E.,
Schulte Johannes H.,
Ochsenreither Sebastian,
Eggert Angelika,
Künkele Annette
Publication year - 2020
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.23202
Subject(s) - biology , neuroblastoma , cancer research , nivolumab , chimeric antigen receptor , immune checkpoint , t cell , microbiology and biotechnology , cell culture , immune system , immunology , immunotherapy , genetics
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.