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

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-beta, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-zeta CAR, but not with a 4-1BB-zeta CAR, resist TGF-beta-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-beta resistance; deleting the LCK-beta inding motif in the CD28 CAR abolished both IL-2 secretion and TGF-beta resistance, while IL-2 add-back restored TGF-beta resistance. Other g-cytokines like IL-7 and IL-15 could replace IL-2 in this context. This is demonstrated by engineering IL-2 deficient CD28DLCK-zeta CAR T cells with a hybrid IL-7 receptor to provide IL-2R beta chain signaling upon IL-7 binding. Such modified T cells showed improved CAR T cell activity against TGF-beta(+) 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-beta(+) solid tumors.