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Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. ​

文献信息 ​

PMID26321679
期刊Cell
影响因子42.5
JCR 分区Q1
发表年份2015
被引次数1691
关键词代谢竞争, 肿瘤微环境, T细胞, 糖酵解, PD-L1
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
ISSN0092-8674
页码1229-41
期号162(6)
作者Chih-Hao Chang, Jing Qiu, David O'Sullivan, Michael D Buck, Takuro Noguchi, Jonathan D Curtis, Qiongyu Chen, Mariel Gindin, Matthew M Gubin, Gerritje J W van der Windt, Elena Tonc, Robert D Schreiber, Edward J Pearce, Erika L Pearce

一句话小结 ​

本研究揭示了肿瘤对葡萄糖的消耗通过限制T细胞的代谢活性，导致其抗肿瘤能力下降，从而促进肿瘤进展。研究表明，使用检查点阻断抗体能够恢复肿瘤微环境中的葡萄糖，增强T细胞的糖酵解和抗肿瘤功能，提供了新的治疗思路。

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代谢竞争 · 肿瘤微环境 · T细胞 · 糖酵解 · PD-L1

摘要 ​

T细胞未能对抗癌症的原因被认为是缺乏抗原识别、慢性激活和/或被其他细胞抑制。通过使用小鼠肉瘤模型，我们展示了肿瘤对葡萄糖的消耗在代谢上限制了T细胞，导致其mTOR活性、糖酵解能力和IFN-γ产生的降低，从而促进了肿瘤的进展。我们表明，在具有抗原性的“回归”肿瘤中增强糖酵解足以覆盖T细胞控制肿瘤生长的保护能力。我们还发现，临床使用的针对CTLA-4、PD-1和PD-L1的检查点阻断抗体可以恢复肿瘤微环境中的葡萄糖，从而允许T细胞进行糖酵解和IFN-γ的产生。此外，我们发现直接在肿瘤上阻断PD-L1会通过抑制mTOR活性和降低糖酵解酶的表达来减弱糖酵解，反映了PD-L1在肿瘤葡萄糖利用中的作用。我们的结果表明，肿瘤施加的代谢限制可以介导癌症期间T细胞的低反应性。

英文摘要 ​

Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.

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主要研究问题 ​

  1. 肿瘤微环境中的代谢竞争如何影响T细胞的功能和抗肿瘤能力？
  2. 在不同类型的肿瘤中，代谢竞争对免疫细胞的影响是否存在差异？
  3. 如何通过调节肿瘤微环境中的代谢状态来增强T细胞的抗肿瘤反应？
  4. 检查点抑制剂如何具体影响肿瘤代谢及其对T细胞功能的恢复？
  5. 未来的治疗策略是否可以利用代谢干预来改善癌症免疫疗法的效果？

核心洞察 ​

研究背景和目的 ​

在癌症免疫治疗中，T细胞的保护作用常因抗原识别不足、慢性激活及其他细胞的抑制而受限。本研究旨在探讨肿瘤对T细胞的代谢限制如何影响其功能，特别是T细胞的mTOR活性、糖酵解能力及干扰素-γ（IFN-γ）产生，从而促进肿瘤进展。

主要方法/材料/实验设计 ​

本研究采用小鼠肉瘤模型，分析肿瘤代谢对T细胞功能的影响。研究设计包括以下几个主要步骤：

Mermaid diagram

关键结果和发现 ​

  1. 肿瘤对T细胞的代谢限制：肿瘤通过消耗葡萄糖，抑制T细胞的mTOR活性和糖酵解能力，降低IFN-γ的产生，促进肿瘤进展。
  2. 糖酵解增强：在抗原性“回归”肿瘤中增强糖酵解足以覆盖T细胞的保护作用，控制肿瘤生长。
  3. 检查点阻断抗体的作用：CTLA-4、PD-1和PD-L1抗体能够恢复肿瘤微环境中的葡萄糖，促进T细胞的糖酵解和IFN-γ产生。
  4. PD-L1的直接作用：直接阻断肿瘤上的PD-L1会抑制糖酵解，减少mTOR活性及糖酵解酶的表达。

主要结论/意义/创新性 ​

本研究表明，肿瘤施加的代谢限制可以导致T细胞功能低下，从而影响抗肿瘤免疫反应。通过恢复肿瘤微环境中的葡萄糖，检查点阻断抗体能够有效提升T细胞的代谢功能和免疫效应。这一发现为改善癌症免疫治疗提供了新的视角，强调了代谢状态在肿瘤免疫逃逸中的重要性。

研究局限性和未来方向 ​

  1. 局限性：

    • 研究主要基于小鼠模型，尚需在人类临床试验中验证。
    • 对不同类型肿瘤的代谢影响及T细胞反应的普遍性需要进一步探讨。

  2. 未来方向：

    • 探索其他代谢途径在T细胞功能中的作用。
    • 研究结合代谢调节与免疫检查点阻断的联合治疗策略。
    • 开发新型药物，针对肿瘤代谢途径进行干预，以提升免疫治疗效果。

参考文献 ​

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引用本文的文献 ​

  1. Nutrient Competition: A New Axis of Tumor Immunosuppression. - Madhusudhanan Sukumar;Rahul Roychoudhuri;Nicholas P Restifo - Cell (2015)
  2. Tumour immunology: An exhausting metabolic competition. - Sarah Seton-Rogers - Nature reviews. Cancer (2015)
  3. Beyond Genomics: Multidimensional Analysis of Cancer Therapy Resistance. - Mary Philip;Andrea Schietinger - Trends in immunology (2015)
  4. Immunometabolism: Cellular Metabolism Turns Immune Regulator. - Róisín M Loftus;David K Finlay - The Journal of biological chemistry (2016)
  5. Costimulation Endows Immunotherapeutic CD8 T Cells with IL-36 Responsiveness during Aerobic Glycolysis. - Naomi Tsurutani;Payal Mittal;Marie-Clare St Rose;Soo Mun Ngoi;Julia Svedova;Antoine Menoret;Forrest B Treadway;Reinhard Laubenbacher;Jenny E Suárez-Ramírez;Linda S Cauley;Adam J Adler;Anthony T Vella - Journal of immunology (Baltimore, Md. : 1950) (2016)
  6. Cholesterol metabolites and tumor microenvironment: the road towards clinical translation. - Laura Raccosta;Raffaella Fontana;Gianfranca Corna;Daniela Maggioni;Marta Moresco;Vincenzo Russo - Cancer immunology, immunotherapy : CII (2016)
  7. Glycolysis and EZH2 boost T cell weaponry against tumors. - Glenn R Bantug;Christoph Hess - Nature immunology (2016)
  8. Immunometabolism governs dendritic cell and macrophage function. - Luke A J O'Neill;Edward J Pearce - The Journal of experimental medicine (2016)
  9. The Warburg Effect: How Does it Benefit Cancer Cells? - Maria V Liberti;Jason W Locasale - Trends in biochemical sciences (2016)
  10. Genetics and biology of pancreatic ductal adenocarcinoma. - Haoqiang Ying;Prasenjit Dey;Wantong Yao;Alec C Kimmelman;Giulio F Draetta;Anirban Maitra;Ronald A DePinho - Genes & development (2016)

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