免疫疗法
癌症研究
嵌合抗原受体
T细胞
CD8型
细胞毒性T细胞
癌症免疫疗法
生物
癌症
过继性细胞移植
免疫学
免疫系统
体外
生物化学
遗传学
作者
Yu Zhang,Vu Trang,Douglas C. Palmer,Rigel J. Kishton,Lanqi Gong,Jiao Huang,Thanh Hung Nguyen,Zuojia Chen,Cari Smith,Ferenc Livák,Rohit Paul,Chi-Ping Day,Chuan Wu,Glenn Merlino,Kenneth Aldape,Xin Yuan Guan,Peng Jiang
出处
期刊:Nature Medicine
[Springer Nature]
日期:2022-05-02
卷期号:28 (7): 1421-1431
被引量:22
标识
DOI:10.1038/s41591-022-01799-y
摘要
Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (tumor-resilient T cell), a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-β1, tumor necrosis factor-related apoptosis-inducing ligand and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in melanoma, lung cancer, triple-negative breast cancer and B cell malignancies using bulk T cell transcriptomic data from pre-treatment tumors from patients who received immune-checkpoint inhibitors (n = 38), infusion products for chimeric antigen receptor T cell therapies (n = 34) and pre-manufacture samples for chimeric antigen receptor T cell or tumor-infiltrating lymphocyte therapies (n = 84). Further, Tres identified FIBP, whose functions are largely unknown, as the top negative marker of tumor-resilient T cells across many solid tumor types. FIBP knockouts in murine and human donor CD8+ T cells significantly enhanced T cell-mediated cancer killing in in vitro co-cultures. Further, Fibp knockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. Fibp knockout T cells exhibit reduced cholesterol metabolism, which inhibits effector T cell function. These results demonstrate the utility of Tres in identifying biomarkers of T cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors.
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