与多种肿瘤类型的免疫治疗反应相关的T细胞韧性模型

2022-06-04 11:11

尽管癌症免疫治疗取得了突破性进展，但由于免疫抑制环境，大多数肿瘤的反应性T细胞无法在实体瘤中持续存在。

SCI

3 June 2022

A T cell resilience model associated with response to immunotherapy in multiple tumor types

（IF: Nature Med., 53.44）

Zhang Y, Trang V, Palmer DC, Kishton RJ, Gong L, Huang J, Nguyen T, Chen Z, Smith C, Livák F, Paul R, Day CP, Wu C, Merlino G, Aldape K, Guan XY, Jiang P. A T cell resilience model associated with response to immunotherapy in multiple tumor types. Nat Med. 2022 May 2.
Correspondence and requests for materials should be addressed to Peng Jiang.

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.

尽管癌症免疫治疗取得了突破性进展，但由于免疫抑制环境，大多数肿瘤的反应性T细胞无法在实体瘤中持续存在。我们开发了Tres（抗肿瘤韧性T细胞），这是一种利用单细胞转录组数据，来识别对免疫抑制信号具有抵抗的T细胞特征的计算模型，如转化生长因子-β1、肿瘤坏死因子相关凋亡与凋亡相关的诱导配体，和前列腺素E2。Tres可靠地预测了黑色素瘤、肺癌、三阴性乳腺癌和B细胞恶性肿瘤对免疫治疗的临床反应，利用来自接受免疫检查点抑制剂（n=38）患者治疗前肿瘤的大量T细胞转录组数据，用于嵌合抗原受体T细胞治疗的输液产品（n=34）和用于嵌合抗原受体T细胞或肿瘤浸润淋巴细胞治疗的预制样品（n=84）。同时，Tres鉴定出，FIBP，是许多实体瘤类型中抗肿瘤T细胞的最高级别阴性标记物，其功能在很大程度上未知。小鼠和人类供体CD8+T细胞中的FIBP基因敲除可显著增强T细胞介导的体外共培养肿瘤杀伤作用。此外，小鼠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疗效。FIBP基因敲除T细胞表现出胆固醇代谢的降低，从而抑制效应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实体瘤免疫治疗的潜在治疗靶点方面的实用性。