An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo.

ABSTRACT: NKp30 is a natural cytotoxicity receptor that is expressed on NK cells and recognizes B7-H6, which is expressed on several types of tumors but few normal cells. To target effector T cells against B7-H6+ tumors, we developed several chimeric AgRs (CARs) based on NKp30, which contain the CD28- and/or CD3?-signaling domains with the transmembrane domains from CD3?, CD28, or CD8?. The data show that chimeric NKp30-expressing T cells responded to B7-H6+ tumor cells. The NKp30 CAR-expressing T cells produced IFN-? and killed B7-H6 ligand-expressing tumor cells; this response was dependent upon ligand expression on target cells but not on MHC expression. PBMC-derived dendritic cells also express NKp30 ligands, including immature dendritic cells, and they can stimulate NKp30 CAR-bearing T cells to produce IFN-?, but to a lesser extent. The addition of a CD28-signaling domain significantly enhanced the activity of the NKp30 CAR in a PI3K-dependent manner. Adoptive transfer of T cells expressing a chimeric NKp30 receptor containing a CD28-signaling domain inhibited the growth of a B7-H6-expressing murine lymphoma (RMA/B7-H6) in vivo. Moreover, mice that remained tumor-free were resistant to a subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor Ags. Overall, this study demonstrates the specificity and therapeutic potential of adoptive immunotherapy with NKp30 CAR-expressing T cells against B7-H6+ tumor cells in vivo.

SUBMITTER: Zhang T 

PROVIDER: S-EPMC3633481 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature