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CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms

ABSTRACT: Compared to CAR.CD19 T cells, we found that CAR.CD19 NKTs showed superior control of tumor growth in the B16-OVA-hCD19 melanoma model without evident toxicity. To investigate whetehr CAR.CD19 NKTs could affect the TME in the tumor. We used the single RNA seq to test the TME cell populations in the B16-OVA-hCD19 model between CAR.CD19 NKTs and CAR.CD19 Ts.

ORGANISM(S): Mus musculus

PROVIDER: GSE236066 | GEO | 2024/08/21

REPOSITORIES: GEO

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CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms

Project description:CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms

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IL-12 Reprograms CAR-Expressing Natural Killer T cells to Long-Lived TH1-Polarized Cells with Potent Antitumor Activity

Project description:Human natural killer T cells (NKTs) are innate-like T lymphocytes that are increasingly used for cancer immunotherapy. Here we show that human NKTs expressing the pro-inflammatory cytokine interleukin-12 (IL-12) undergo extensive and sustained molecular and functional reprogramming. Specifically, IL-12 instructs and maintain a Th1-polarization program in NKTs in vivo without causing their functional exhaustion. Furthermore, using CD62L as a marker of memory cells in human NKTs, we observed that IL-12 maintains long-term CD62L-expressing memory NKTs in vivo. Notably, IL-12 initiates de novo programming of memory NKTs in CD62L negative NKTs indicating that human NKTs circulating in the peripheral blood possess an intrinsic differentiation hierarchy and that IL-12 plays a role in promoting their differentiation to long-lived Th1-polarized memory cells. Human NKTs engineered to co-express a Chimeric Antigen Receptor (CAR) coupled with the expression of IL-12 showed enhanced antitumor activity in tumor models, persisted long-term in vivo and conserved the molecular signature driven by the IL-12 expression. Thus IL-12 reveals an intrinsic and unappreciated plasticity of peripheral human NKTs that may play a crucial role in the development of cell therapeutics.

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