4-1BB costimulation promotes CAR T cell survival through noncanonical NF-{kappa}B signaling

Clinical response to chimeric antigen receptor (CAR) T cell therapy is correlated with CAR T cell persistence, especially for CAR T cells that target CD19+ hematologic malignancies. 4-1BB–costimulated CAR (BB) T cells exhibit longer persistence after adoptive transfer than do CD28-costimulated CAR (28) T cells. 4-1BB signaling improves T cell persistence even in the context of 28 CAR activation, which indicates distinct prosurvival signals mediated by the 4-1BB cytoplasmic domain. To specifically study signal transduction by CARs, we developed a cell-free, ligand-based activation and ex vivo culture system for CD19-specific CAR T cells. We observed greater ex vivo survival and subsequent expansion of BB CAR T cells when compared to 28 CAR T cells. We showed that only BB CARs activated noncanonical nuclear factor B (ncNF-B) signaling in T cells basally and that the anti-CD19 BB CAR further enhanced ncNF-B signaling after ligand engagement. Reducing ncNF-B signaling reduced the expansion and survival of anti-CD19 BB T cells and was associated with a substantial increase in the abundance of the most pro-apoptotic isoforms of Bim. Although our findings do not exclude the importance of other signaling differences between BB and 28 CARs, they demonstrate the necessary and nonredundant role of ncNF-B signaling in promoting the survival of BB CAR T cells, which likely underlies the engraftment persistence observed with this CAR design.
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news