Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
EMBO J. 2023 Mar 1;42(5):e111614. doi: 10.15252/embj.2022111614. Epub 2023 Jan 30.
Resistance to cancer immunotherapy continues to impair common clinical benefit. Here, we use whole-genome CRISPR-Cas9 knockout data to uncover an important role for Tuberous Sclerosis Complex 2 (TSC2) in determining tumor susceptibility to cytotoxic T lymphocyte (CTL) killing in human melanoma cells. TSC2-depleted tumor cells had disrupted mTOR regulation following CTL attack, which was associated with enhanced cell death. Wild-type tumor cells adapted to CTL attack by shifting their mTOR signaling balance toward increased mTORC2 activity, circumventing apoptosis, and necroptosis. TSC2 ablation strongly augmented tumor cell sensitivity to CTL attack in vitro and in vivo, suggesting one of its functions is to critically protect tumor cells. Mechanistically, TSC2 inactivation caused elevation of TRAIL receptor expression, cooperating with mTORC1-S6 signaling to induce tumor cell death. Clinically, we found a negative correlation between TSC2 expression and TRAIL signaling in TCGA patient cohorts. Moreover, a lower TSC2 immune response signature was observed in melanomas from patients responding to immune checkpoint blockade. Our study uncovers a pivotal role for TSC2 in the cancer immune response by governing crosstalk between TSC2-mTOR and TRAIL signaling, aiding future therapeutic exploration of this pathway in immuno-oncology.
癌症免疫疗法的耐药性持续阻碍着临床获益。在这里，我们使用全基因组 CRISPR-Cas9 敲除数据，揭示了结节性硬化复合物 2（TSC2）在决定人类黑色素瘤细胞对细胞毒性 T 淋巴细胞（CTL）杀伤的肿瘤易感性方面的重要作用。TSC2 耗竭的肿瘤细胞在 CTL 攻击后出现 mTOR 调节紊乱，这与增强的细胞死亡有关。野生型肿瘤细胞通过将其 mTOR 信号平衡转向增加 mTORC2 活性来适应 CTL 攻击，从而避免细胞凋亡和坏死。TSC2 缺失强烈增强了肿瘤细胞对 CTL 攻击的敏感性，无论是在体外还是体内，这表明其功能之一是关键地保护肿瘤细胞。从机制上讲，TSC2 失活导致 TRAIL 受体表达升高，与 mTORC1-S6 信号协同诱导肿瘤细胞死亡。临床上，我们在 TCGA 患者队列中发现 TSC2 表达与 TRAIL 信号之间存在负相关。此外，在对免疫检查点阻断有反应的患者的黑色素瘤中观察到较低的 TSC2 免疫反应特征。我们的研究通过调节 TSC2-mTOR 和 TRAIL 信号之间的串扰，揭示了 TSC2 在癌症免疫反应中的关键作用，有助于该途径在肿瘤免疫治疗中的进一步探索。
