journal contribution
posted on 2024-03-11, 14:20 authored by Shintaro Kinoshita, Midori Ishii, Jun Ando, Takaharu Kimura, Tomoyuki Yamaguchi, Sakiko Harada, Fumiyuki Takahashi, Kazutaka Nakashima, Yozo Nakazawa, Satoshi Yamazaki, Koichi Ohshima, Kazuhisa Takahashi, Hiromitsu Nakauchi, Miki Ando Supplementary Figure S3 demonstrates the expression profiles of signature genes (including lineage, co-stimulation, co-inhibition, cytotoxic molecules, and transcription factors) in GD2-2840z-CARTs, GD2-CARrejTs, and control T cells through a heatmap. It also includes UMAP projections of CITE-seq data highlighting the distribution of CD3, CD4, and CD8 markers, and phenotypic markers specific to GD2-2840z-CARTs and GD2-CARrejTs. Additionally, a heatmap showcases the expression of chemokine receptor-related genes in these cell types, providing insights into their functional characteristics.
Funding
MEXT | Japan Society for the Promotion of Science (JSPS)
Ludwig Family Foundation (The Ludwig Family Foundation)
History
ARTICLE ABSTRACT
Small cell lung cancer (SCLC) is exceptionally aggressive, with limited treatment options. Disialoganglioside (GD2) is highly expressed on SCLC and is considered a good target for chimeric antigen receptor (CAR) T cells (CART). Although GD2-directed CARTs (GD2-CART) exhibit cytotoxicity against various GD2-expressing tumors, they lack significant cytotoxicity against SCLC. To enhance cytotoxicity of GD2-CARTs against SCLC, we introduced GD2-CAR into induced pluripotent stem cells (iPSC)-derived rejuvenated cytotoxic T lymphocytes (GD2-CARrejT). GD2-CARrejTs acted much more strongly against SCLC cells than did GD2-CARTs both in vitro and in vivo. Single-cell RNA sequencing elucidated that levels of expression of TIGIT were significantly lower and levels of expression of genes associated with cytotoxicity were significantly higher in GD2-CARrejTs than those in GD2-CARTs. Dual blockade of TIGIT and programmed death-1 (PD-1) increased the cytotoxicity of GD2-CARTs to some extent, suggesting that low TIGIT and PD-1 expression by GD2-CARrejTs is a major factor required for robust cytotoxicity against SCLC. Not only for robust cytotoxicity but also for availability as “off-the-shelf” T-cell therapy, iPSC-derived GD2-CARrejTs are a promising novel treatment for SCLC.
This research introduces iPSC-derived rejuvenated GD2-CARTs (GD2-CARrejT) as a novel approach to combat SCLC. Compared with conventional GD2-CARTs, GD2-CARrejTs with reduced TIGIT and PD-1 expression demonstrate robust cytotoxicity against SCLC and would be a promising therapy for SCLC.
