抑制硬脂酰辅酶A去饱和酶 1 (SCD1) 通过调节癌细胞中的 β-连环蛋白信号和 T 细胞中的 ER 应激增强抗肿瘤 T 细胞反应，并与抗 PD-1 抗体协同作用。,Journal for ImmunoTherapy of Cancer

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抑制硬脂酰辅酶A去饱和酶 1 (SCD1) 通过调节癌细胞中的 β-连环蛋白信号和 T 细胞中的 ER 应激增强抗肿瘤 T 细胞反应，并与抗 PD-1 抗体协同作用。
Journal for ImmunoTherapy of Cancer ( IF 10.3 ) Pub Date : 2022-07-01 , DOI: 10.1136/jitc-2022-004616
Yuki Katoh _{1,

2} , Tomonori Yaguchi ₃ , Akiko Kubo ₄ , Takashi Iwata _{1,

5} , Kenji Morii ₁ , Daiki Kato _{1,

6} , Shigeki Ohta ₁ , Ryosuke Satomi ₇ , Yasuhiro Yamamoto ₈ , Yoshitaka Oyamada ₇ , Kota Ouchi _{9,

10} , Shin Takahashi _{9,

10} , Chikashi Ishioka _{9,

10} , Ryo Matoba ₁₁ , Makoto Suematsu ₄ , Yutaka Kawakami _{3,

12}

Affiliation

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
Division of Anatomical Science, Department of Functional Morphology, Nihon University School of Medicine, Tokyo, Japan.
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
National Hospital Organisation Tokyo Medical Center, Tokyo, Japan.
Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan.
Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
DNA Chip Research Inc, Tokyo, Japan.
Department of Immunology, International University of Health and Welfare, Chiba, Japan.

背景了解非 T 细胞炎症性肿瘤微环境 (TME) 的机制及其调节对于改善癌症免疫疗法（如免疫检查点抑制剂）具有重要意义。最近已经表明各种免疫代谢的参与在免疫抑制性 TME 的形成中。在这项研究中，我们研究了对脂肪酸代谢至关重要的硬脂酰辅酶 A 去饱和酶 1 (SCD1) 在癌症免疫反应中的免疫学作用。方和分子机制。SCD1 在人类癌症中的作用也通过结肠癌组织的基因表达分析和评估从接受抗 PD-1 抗体治疗的非小细胞肺癌患者血清中的相关游离脂肪酸来研究。结果在小鼠肿瘤模型中全身给药 SCD1 抑制剂通过减少 Wnt/β-连环蛋白信号传导和 CD8+ 效应 T 细胞通过减少内质网应激增强了癌细胞 CCL4 的产生。它反过来促进树突状细胞 (DC) 募集到肿瘤中，并增强随后的抗肿瘤 CD8+ T 细胞的诱导和肿瘤积累。还发现 SCD1 抑制剂可直接刺激 DC 和 CD8+ T 细胞。在小鼠中施用 SCD1 抑制剂或 SCD1 敲除与抗 PD-1 抗体协同作用在小鼠肿瘤模型中的抗肿瘤作用。在人结肠癌的一种非 T 细胞炎症亚型中观察到 SCD1 高表达，血清 SCD1 相关脂肪酸与非小肺癌患者抗 PD-1 抗体治疗后的反应率和预后相关. 结论在癌细胞和免疫细胞中表达的 SCD1 会引起免疫抵抗，其抑制作用增强了抗肿瘤 T 细胞和抗 PD-1 抗体的治疗效果。因此，SCD1 是开发新的诊断和治疗策略以改善包括免疫检查点抑制剂在内的当前癌症免疫疗法的有吸引力的目标。在人结肠癌的一种非 T 细胞炎症亚型中观察到 SCD1 高表达，血清 SCD1 相关脂肪酸与非小肺癌患者抗 PD-1 抗体治疗后的反应率和预后相关. 结论在癌细胞和免疫细胞中表达的 SCD1 会引起免疫抵抗，其抑制作用增强了抗肿瘤 T 细胞和抗 PD-1 抗体的治疗效果。因此，SCD1 是开发新的诊断和治疗策略以改善包括免疫检查点抑制剂在内的当前癌症免疫疗法的有吸引力的目标。在人结肠癌的一种非 T 细胞炎症亚型中观察到 SCD1 高表达，血清 SCD1 相关脂肪酸与非小肺癌患者抗 PD-1 抗体治疗后的反应率和预后相关. 结论在癌细胞和免疫细胞中表达的 SCD1 会引起免疫抵抗，其抑制作用增强了抗肿瘤 T 细胞和抗 PD-1 抗体的治疗效果。因此，SCD1 是开发新的诊断和治疗策略以改善包括免疫检查点抑制剂在内的当前癌症免疫疗法的有吸引力的目标。结论在癌细胞和免疫细胞中表达的 SCD1 会引起免疫抵抗，其抑制作用增强了抗肿瘤 T 细胞和抗 PD-1 抗体的治疗效果。因此，SCD1 是开发新的诊断和治疗策略以改善包括免疫检查点抑制剂在内的当前癌症免疫疗法的有吸引力的目标。结论在癌细胞和免疫细胞中表达的 SCD1 会引起免疫抵抗，其抑制作用增强了抗肿瘤 T 细胞和抗 PD-1 抗体的治疗效果。因此，SCD1 是开发新的诊断和治疗策略以改善包括免疫检查点抑制剂在内的当前癌症免疫疗法的有吸引力的目标。

"点击查看英文标题和摘要"

Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody.

BACKGROUND Understanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response. METHODS We investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody. RESULTS Systemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/β-catenin signaling and by CD8+ effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8+ T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8+ T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment. CONCLUSIONS SCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.

更新日期：2022-07-01

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