4-1BB costimulation promotes CAR T cell survival through noncanonical NF-?B signaling.

ABSTRACT: 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.

SUBMITTER: Philipson BI 

PROVIDER: S-EPMC7883633 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature