期刊
JOURNAL OF IMMUNOLOGY
卷 201, 期 7, 页码 2141-2153出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1800429
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类别
资金
- National Institutes of Health [R01 CA116548, P50 CA126752, S10 OD020066]
- Cell Medica, Ltd.
T cells expressing CD19-specific chimeric Ag receptors (CARs) produce high remission rates in B cell lymphoma, but frequent disease recurrence and challenges in generating sufficient numbers of autologous CAR T cells necessitate the development of alternative therapeutic effectors. Va24-invariant NKTs have intrinsic antitumor properties and are not alloreactive, allowing for off-the-shelf use of CAR-NKTs from healthy donors. We recently reported that CD62L(+) NKTs persist longer and have more potent antilymphoma activity than CD62L(-) cells. However, the conditions governing preservation of CD62L(+) cells during NKT cell expansion remain largely unknown. In this study, we demonstrate that IL-21 preserves this crucial central memory-like NKT subset and enhances its antitumor effector functionality. We found that following antigenic stimulation with a-galactosylceramide, CD62L(+) NKTs both expressed IL-21R and secreted IL-21, each at significantly higher levels than CD62L(-) cells. Although IL-21 alone failed to expand stimulated NKTs, combined IL-2/IL-21 treatment produced more NKTs and increased the frequency of CD62L(+) cells versus IL-2 alone. Gene expression analysis comparing CD62L(+) and CD62L(-) cells treated with IL-2 alone or IL-2/IL-21 revealed that the latter condition downregulated the proapoptotic protein BIM selectively in CD62L(+) NKTs, protecting them from activation-induced cell death. Moreover, IL-2/IL-21-expanded NKTs upregulated granzyme B expression and produced more T(H)1 cytokines, leading to enhanced in vitro cytotoxicity of nontransduced and anti-CD19-CAR-transduced NKTs against CD1d(+) and CD19(+) lymphoma cells, respectively. Further, IL-2/IL-21-expanded CAR-NKTs dramatically increased the survival of lymphoma-bearing NSG mice compared with IL-2-expanded CAR-NKTs. These findings have immediate translational implications for the development of NKT cell-based immunotherapies targeting lymphoma and other malignancies.
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