CD28-ζ CAR T Cells Resist TGF-β 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-β, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-ζ CAR, but not with a 4-1BB-ζ CAR, resist TGF-β-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-β resistance; deleting the LCK-binding motif in the CD28 CAR abolished both IL-2 secretion and TGF-β resistance, while IL-2 add-back restored TGF-β resistance. Other γ-cytokines like IL-7 and IL-15 could replace IL-2 in this context. This is demonstrated by engineering IL-2

SUBMITTER: Golumba-Nagy V 

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

REPOSITORIES: biostudies-literature