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Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment.
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-04-25 , DOI: 10.1016/j.cmet.2019.04.002 Xingzhe Ma 1 , Enguang Bi 1 , Yong Lu 2 , Pan Su 1 , Chunjian Huang 1 , Lintao Liu 1 , Qiang Wang 1 , Maojie Yang 1 , Matthew F Kalady 3 , Jianfei Qian 1 , Aijun Zhang 4 , Anisha A Gupte 4 , Dale J Hamilton 4 , Chengyun Zheng 5 , Qing Yi 1
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-04-25 , DOI: 10.1016/j.cmet.2019.04.002 Xingzhe Ma 1 , Enguang Bi 1 , Yong Lu 2 , Pan Su 1 , Chunjian Huang 1 , Lintao Liu 1 , Qiang Wang 1 , Maojie Yang 1 , Matthew F Kalady 3 , Jianfei Qian 1 , Aijun Zhang 4 , Anisha A Gupte 4 , Dale J Hamilton 4 , Chengyun Zheng 5 , Qing Yi 1
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Tumor-infiltrating T cells often lose their effector function; however, the mechanisms are incompletely understood. We report that cholesterol in the tumor microenvironment induces CD8+T cell expression of immune checkpoints and exhaustion. Tumor tissues enriched with cholesterol and cholesterol content in tumor-infiltrating CD8+T cells were positively and progressively associated with upregulated T cell expression of PD-1, 2B4, TIM-3, and LAG-3. Adoptively transferred CD8+T cells acquired cholesterol, expressed high levels of immune checkpoints, and became exhausted upon entering a tumor. Tumor culture supernatant or cholesterol induced immune checkpoint expression by increasing endoplasmic reticulum (ER) stress in CD8+T cells. Consequently, the ER stress sensor XBP1 was activated and regulated PD-1 and 2B4 transcription. Inhibiting XBP1 or reducing cholesterol in CD8+T cells effectively restored antitumor activity. This study reveals a mechanism underlying T cell exhaustion and suggests a new strategy for restoring T cell function by reducing cholesterol to enhance T cell-based immunotherapy.
中文翻译：
胆固醇在肿瘤微环境中诱导CD8 + T细胞耗尽。
肿瘤浸润性T细胞通常会丧失其效应子功能。但是，机制尚不完全清楚。我们报告肿瘤微环境中的胆固醇诱导免疫检查点和疲劳的CD8 + T细胞表达。肿瘤浸润的CD8 + T细胞中富含胆固醇和胆固醇含量的肿瘤组织与PD-1、2B4，TIM-3和LAG-3的T细胞表达上调正相关并逐步相关。过继转移的CD8 + T细胞获得胆固醇，表达高水平的免疫检查点，并在进入肿瘤后变得精疲力尽。肿瘤培养上清液或胆固醇通过增加CD8 + T细胞中的内质网（ER）应激来诱导免疫检查点表达。因此，ER压力传感器XBP1被激活并调节PD-1和2B4转录。抑制XBP1或降低CD8 + T细胞中的胆固醇可有效恢复抗肿瘤活性。这项研究揭示了T细胞衰竭的潜在机制，并提出了一种通过降低胆固醇以增强基于T细胞的免疫疗法来恢复T细胞功能的新策略。
更新日期：2019-05-16
中文翻译：
胆固醇在肿瘤微环境中诱导CD8 + T细胞耗尽。
肿瘤浸润性T细胞通常会丧失其效应子功能。但是，机制尚不完全清楚。我们报告肿瘤微环境中的胆固醇诱导免疫检查点和疲劳的CD8 + T细胞表达。肿瘤浸润的CD8 + T细胞中富含胆固醇和胆固醇含量的肿瘤组织与PD-1、2B4，TIM-3和LAG-3的T细胞表达上调正相关并逐步相关。过继转移的CD8 + T细胞获得胆固醇，表达高水平的免疫检查点，并在进入肿瘤后变得精疲力尽。肿瘤培养上清液或胆固醇通过增加CD8 + T细胞中的内质网（ER）应激来诱导免疫检查点表达。因此，ER压力传感器XBP1被激活并调节PD-1和2B4转录。抑制XBP1或降低CD8 + T细胞中的胆固醇可有效恢复抗肿瘤活性。这项研究揭示了T细胞衰竭的潜在机制，并提出了一种通过降低胆固醇以增强基于T细胞的免疫疗法来恢复T细胞功能的新策略。
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