<br>靶向α-酮戊二酸破坏克服了免疫逃避并改善了肾细胞癌的 PD-1 阻断免疫治疗,Advanced Science

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靶向α-酮戊二酸破坏克服了免疫逃避并改善了肾细胞癌的 PD-1 阻断免疫治疗
Advanced Science ( IF 14.3 ) Pub Date : 2023-08-01 , DOI: 10.1002/advs.202301975
Le Li _{1,

2} , Xing Zeng ₁ , Zheng Chao _{1,

2} , Jing Luo ₃ , Wei Guan ₁ , Qiang Zhang ₄ , Yue Ge ₁ , Yanan Wang ₁ , Zezhong Xiong ₁ , Sheng Ma ₁ , Qiang Zhou ₁ , Junbiao Zhang ₁ , Jihua Tian ₁ , David Horne ₅ , Bertram Yuh ₅ , Zhiquan Hu ₁ , Gong-Hong Wei ₆ , Baojun Wang ₇ , Xu Zhang ₇ , Peixiang Lan ₂ , Zhihua Wang ₁

Affiliation

Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China.
Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. China.
Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
Fudan University Shanghai Cancer Center & MOE Key Laboratory of Metabolism and Molecular Medicine and Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
Department of Urology, the Third Medical Center, Chinese PLA General Hospital, No.39 Yongding Road, Beijing, 100039, China.

与瓦尔堡效应相关的三羧酸（TCA）循环代谢功能障碍已成为各种实体瘤，特别是肾细胞癌（RCC）的标志。 RCC 的特点是高免疫浸润，因此临床指南建议在晚期进行免疫治疗干预。然而，免疫疗法的有限益处促使人们对潜在机制进行研究，从而提出代谢失调诱导的免疫逃避是一个关键因素。在这项研究中，发现α-酮戊二酸 (αKG) 的丰度显着下降，α-酮戊二酸 (αKG) 是 TCA 循环中至关重要的中间代谢产物，与临床 RCC 样本中的较高分级和较差预后相关。 αKG 水平升高可促进主要组织相容性复合体-I (MHC-I) 抗原的加工和呈递，以及 β2-微球蛋白 (B2M) 的表达。虽然 αKG 调节组蛋白的广谱去甲基化活性，但 B2M 的转录上调依赖于其启动子区域 H3K4me1 的去甲基化。此外，与单一疗法相比，补充 αKG 和 PD-1 阻断相结合可提高小鼠模型的治疗效果并延长生存期。总体而言，这些发现阐明了抗肿瘤免疫疗法中免疫逃避的机制，并提出了 RCC 的潜在组合治疗策略。

"点击查看英文标题和摘要"

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

更新日期：2023-08-01

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