CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing.
Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing.
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TIL（肿瘤浸润淋巴细胞）疗法是一种过继细胞治疗：从患者肿瘤中获取淋巴细胞，在体外通过IL-2刺激大量扩增后再回输患者（Rosenberg和Restifo，2015，Science 348:62–68；Bonini和Mondino，2015，Eur. J. Immunol. 45:2457–69）。
然而，即使使用TIL治疗，癌细胞仍可因淋巴细胞浸润不足、T细胞受体长期活化及免疫抑制性肿瘤微环境等原因存活（Morgan等，1976，Science 193:1007–8）。细胞因子诱导的含SH2结构域蛋白（CISH）是T细胞活化的负调节因子，近期临床试验在TIL中敲除CISH以提高疗效（Rosenberg等，1985，J. Exp. Med. 161:1169–88）。
本研究开发机制性信号通路模型，从理论上评估CISH敲除（CISH KO）对T细胞活化的作用，并考察是否存在可通过多重基因编辑或药物靶向的替代基因，以进一步增强T细胞活化和功能（Donohue等，1984，J. Immunol. 132:2123–8）。
结果显示，CISH敲除可提高活化标志物IL-2和TNF-α的转录，但也会增加PD-1和FasL等抑制性标志物。全局敏感性分析还预测，敲除负责使NFAT失活的GSK3B可进一步增强T细胞活化。
此外，模型预测，与CISH联合敲除PDCD1、FAS和CTLA4，可进一步增强T细胞活化并预防耗竭和凋亡。
Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy, where the lymphocytes of a cancer patient's tumor are harvested, expanded in vitro using IL-2 stimulation, and then infused back into the patient Rosenberg and Restifo (2015 Science 348 62-68), Bonini and Mondino (2015 Eur. J. Immunol. 45 2457-69).
However, even with the use of TIL therapy, cancer cells can survive for various reasons, such as poor lymphocyte infiltration into tumors, chronic activation of the T cell receptor and the immunosuppressive tumor microenvironment Morgan et al (1976 Science 193 1007-8). Cytokine-inducible SH2-containing (CISH) protein is a negative regulator of T cell activation, and in a recent clinical trial was knocked out in TILs to improve TIL therapy efficacy Rosenberg et al (1985 J. Exp. Med. 161 1169-88).
A mechanistic signaling pathway model was developed to theoretically evaluate the efficacy of CISH knockout ( CISH KO) in T cell activation and examine potential alternative target genes that can theoretically be targeted using multiplex gene-editing or drugs to further improve T cell activation and function Donohue et al (1984 J. Immunol. 132 2123-8).
Based on the results, CISH knockout increases the transcription of activation biomarkers IL-2 and TNF- , but also inhibitory biomarkers such as PD1 and FasL. Using global sensitivity analysis, we also found that GSK3B , which is responsible for the deactivation of NFAT, is also predicted to further increase T cell activation when knocked out.
In addition, it was predicted that PDCD1, FAS and CTLA4 can be knocked out in combination with CISH to further enhance T cell activation and prevent exhaustion and apoptosis.
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