Generation of iPSC-derived CD4+ Th1 cells enhancing chimeric antigen receptor-T cell cytotoxicity

Furukawa, Y.; Ishii, M.; Kinoshita, S.; Goto, A.; Izumi, N.; Matsuzaki, K.; Yanashima, K.; Toyota, T.; Tachibana, K.; Ando, J.; Nakauchi, H.; Ando, M.

doi:10.1101/2025.04.24.650471

bioRxiv · 10.1101/2025.04.24.650471

Generation of iPSC-derived CD4+ Th1 cells enhancing chimeric antigen receptor-T cell cytotoxicity

Furukawa, Y.·Ishii, M.·Kinoshita, S.·Goto, A.·Izumi, N.·Matsuzaki, K.·Yanashima, K.·Toyota, T.·Tachibana, K.·Ando, J.·Nakauchi, H.·Ando, M.

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Abstract

CD4+ T cells are anticipated to enhance the overall immune response, including the anti-tumor activity of chimeric antigen receptor (CAR)-T cell therapy. In the past, we established a culture system to generate CD8+ T cells from iPS cells (iPSCs); however, it was challenging to generate CD4+ T cells. Drawing inspiration from the observation that adult T cell leukemia (ATL) cells are consistently CD4+ and possess Treg characteristics, we successfully generated CD4+ Treg cells by reprogramming ATL cells into iPSCs and then differentiating them into T cells. Gene expression analysis of this generation system suggested that RUNX3 serves as a key regulator in T cell differentiation within the ex vivo generation system. By knocking out RUNX3, we demonstrated the generation of antigen-specific CD4+ Th1 cells via the iPSC route, thereby enhancing the activity of CD8+ CAR-T cells against GD2-expressing lymphoma. These technologies hold significant promise for contributing to "off-the-shelf" immunotherapies against malignant tumors, including solid tumors.

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Furukawa, Y., Ishii, M., Kinoshita, S., Goto, A., Izumi, N., Matsuzaki, K., Yanashima, K., Toyota, T., Tachibana, K., Ando, J., Nakauchi, H., Ando, M.. 2025-04-26. Generation of iPSC-derived CD4+ Th1 cells enhancing chimeric antigen receptor-T cell cytotoxicity. https://doi.org/10.1101/2025.04.24.650471

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