CD28-? CAR T Cells Resist TGF-? Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop.

ABSTRACT: Adoptive cell therapy with chimeric antigen receptor (CAR)-redirected T cells induced spectacular regressions of leukemia and lymphoma, however, failed so far in the treatment of solid tumors. A cause is thought to be T cell repression through TGF-?, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-? CAR, but not with a 4-1BB-? CAR, resist TGF-?-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-? resistance; deleting the LCK-binding motif in the CD28 CAR abolished both IL-2 secretion and TGF-? resistance, while IL-2 add-back restored TGF-? resistance. Other ?-cytokines like IL-7 and IL-15 could replace IL-2 in this context. This is demonstrated by engineering IL-2 deficient CD28?LCK-? CAR T cells with a hybrid IL-7 receptor to provide IL-2R ? chain signaling upon IL-7 binding. Such modified T cells showed improved CAR T cell activity against TGF-?⁺ tumors. Data draw the concept that an autocrine loop resulting in IL-2R signaling can make CAR T cells more potent in staying active against TGF-?⁺ solid tumors.

SUBMITTER: Golumba-Nagy V 

PROVIDER: S-EPMC6127517 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature