A T cell resilience model associated with response to immunotherapy in multiple tumor types.
A T cell resilience model associated with response to immunotherapy in multiple tumor types.
复制标题
一种与多种肿瘤类型对免疫疗法的反应相关的T细胞恢复力模型
DOI：
10.1038/s41591-022-01799-y
复制
发表时间：
2022-07
期刊：
影响因子：
82.9
通讯作者：
Jiang, Peng
中科院分区：
文献类型：
--
作者：
Zhang, Yu;Trang, Vu;Palmer, Douglas C.;Kishton, Rigel J.;Gong, Lanqi;Huang, Jiao;Nguyen, Thanh;Chen, Zuojia;Smith, Cari;Livak, Ferenc;Paul, Rohit;Day, Chi-Ping;Wu, Chuan;Merlino, Glenn;Aldape, Kenneth;Guan, Xin-yuan;Jiang, Peng
尽管癌症免疫治疗取得了突破，但由于免疫抑制环境，大多数肿瘤反应性T细胞不能在实体瘤中持续存在。我们开发了Tres（肿瘤弹性T细胞，https：//tumor-resilientT cell，https：//tumor-resilientT cell，ccr.cancer.gov/），这是一种利用单细胞转录组学数据来识别对免疫抑制信号（如转化生长因子-β1、肿瘤坏死因子相关凋亡诱导配体和前列腺素E2）具有弹性的T细胞特征的计算模型。Tres使用来自接受免疫检查点抑制剂的患者（n = 38）的治疗前肿瘤的大量T细胞转录组学数据可靠地预测黑色素瘤、肺癌、三阴性乳腺癌和B细胞恶性肿瘤对免疫疗法的临床应答，用于嵌合抗原受体T细胞疗法输注产品（n = 34）和用于嵌合抗原受体T细胞或肿瘤的预制造样品-浸润性淋巴细胞疗法（n = 84）。此外，Tres确定了FIB，其功能在很大程度上是未知的，作为许多实体瘤类型中肿瘤弹性T细胞的顶级阴性标志物。在体外共培养中，鼠和人供体CD 8 + T细胞中的FIB敲除显著增强T细胞介导的癌症杀伤。此外，鼠T细胞中的Fibp敲除增强了B16肿瘤模型中过继细胞转移的体内功效。Fibp敲除T细胞表现出降低的胆固醇代谢，其抑制效应T细胞功能。这些结果证明了Tres在鉴定T细胞有效性的生物标志物和用于实体瘤中免疫疗法的潜在治疗靶标中的效用。
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, https://resilience.ccr.cancer.gov/), 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.
登录
查看更多内容
FIBP 敲低可通过调节 GSK3beta 相关途径来减弱结直肠癌的生长并增强化疗效果。
影响因子：
6.2
作者：
Huang YF;Niu WB;Hu R;Wang LJ;Huang ZY;Ni SH;Wang MQ;Yang Y;Huang YS;Feng WJ;Xiao W;Zhu DJ;Xian SX;Lu L
通讯作者：
Lu L
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
64.5
作者：
Good CR;Aznar MA;Kuramitsu S;Samareh P;Agarwal S;Donahue G;Ishiyama K;Wellhausen N;Rennels AK;Ma Y;Tian L;Guedan S;Alexander KA;Zhang Z;Rommel PC;Singh N;Glastad KM;Richardson MW;Watanabe K;Tanyi JL;O'Hara MH;Ruella M;Lacey SF;Moon EK;Schuster SJ;Albelda SM;Lanier LL;Young RM;Berger SL;June CH
通讯作者：
June CH
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
64.5
作者：
Dong, Matthew B.;Wang, Guangchuan;Chen, Sidi
通讯作者：
Chen, Sidi