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Distinct functions of CAR-T cells possessing a dectin-1 intracellular signaling domain

Gene Therapy volume 30, pages 411–420 (2023)Cite this article

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Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacies in treating hematopoietic malignancies, but not in the solid tumors. Incorporating costimulatory signaling domains, such as ICOS or 4-1BB, can positively influence CAR-T cell functions and then the immune responses. These CAR-engineered T cells have showed their enhanced persistence and effector functions with improved antitumor activities, and provided a new approach for the treatment of solid tumors. Here, we designed novel 2nd generation CARs with a costimulatory signaling molecule, dectin-1. The impacts of dectin-1 signaling domain on CAR-T cells were evaluated in vitro and in vivo. Our data show that in vitro cytokine secretions by HER2 or CD19 specific CAR-T cells increase significantly via incorporating this dectin-1 signaling domain. Additional properties of these novel CAR-T cells are affected by this costimulatory domain. Compared with a popular reference (i.e., anti-HER2 CAR-T cells with 4-1BB), in vitro T cell functions and in vivo antitumor activity of the dectin-1 engineered CAR-T cells are similar to the 4-1BB based, and both are discrete to the mock T cells. Furthermore, we found that the CAR-T cells with dectin-1 show distinct phenotype and exhaustion marker expression. These collective results suggest that the incorporation of this new signaling domain, dectin-1, into the CARs may provide the clinical potential of the CAR-T cells through this signaling domain in treating solid tumors.

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Fig. 1: CAR constructs and expression.
Fig. 2: In vitro cytokine production and cytotoxicity of the CAR-T cells.
Fig. 3: Phenotype, exhaustion marker expression, and CAR expression of the HER2 specific CAR-T cells.
Fig. 4: In vivo antitumor activity of the HER2 specific CAR-T cells.

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Acknowledgements

This work is supported by the National Key Research and Development Program of China (2016YFC1303403), the National Natural and Scientific Foundation of China 81972878, 81572981, 81672397 and 81703057, the National High-tech R&D program (863 Program) 2014AA020704, the Key Scientific and Technological Foundation in Sichuan Province, 17ZDZX0037.

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  1. Department of Head & Neck Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Xiao Liang & Nianyong Chen

  2. State Key Laboratory of Biotherapy/Collaborative Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Yong Huang, Dan Li, Xiao Yang, Lin Jiang, Weilin Zhou, Jinhua Su & Wei Wang

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Correspondence to Wei Wang.

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WW has submitted a patent concerning the methodology and application. WW is one of the scientific co-founders of Cygenpeutics and CarEne and holds the equity of the company. The authors declare no competing interests.

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Liang, X., Huang, Y., Li, D. et al. Distinct functions of CAR-T cells possessing a dectin-1 intracellular signaling domain. Gene Ther 30, 411–420 (2023). https://doi.org/10.1038/s41434-021-00257-7

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