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The tumor microenvironment and its role in promoting tumor growth. ​

文献信息 ​

DOI10.1038/onc.2008.271
PMID18836471
期刊Oncogene
影响因子7.3
JCR 分区Q1
发表年份2008
被引次数1158
关键词肿瘤微环境, 免疫细胞, 肿瘤逃逸, NF-kappaB通路, 治疗策略
文献类型Journal Article, Research Support, N.I.H., Extramural, Review
ISSN0950-9232
页码5904-12
期号27(45)
作者T L Whiteside

一句话小结 ​

本研究探讨了肿瘤微环境中免疫细胞的功能失调及其对肿瘤生长的促进作用，揭示了NF-kappaB通路在免疫细胞无效激活和肿瘤逃逸中的关键角色。通过深入理解肿瘤微环境的细胞和分子机制，研究为开发新的治疗策略提供了可能，以改变微环境以支持有效的抗肿瘤反应。

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肿瘤微环境 · 免疫细胞 · 肿瘤逃逸 · NF-kappaB通路 · 治疗策略

摘要 ​

肿瘤微环境是由肿瘤形成并主导于肿瘤诱导的相互作用。尽管各种免疫效应细胞被招募到肿瘤部位，但它们的抗肿瘤功能却被下调，这在很大程度上是对肿瘤衍生信号的反应。存在于人类肿瘤中的炎症细胞浸润本质上是慢性的，并且富含调节性T细胞（T(reg)）和髓源抑制细胞（MSC）。肿瘤微环境中的免疫细胞不仅未能发挥抗肿瘤效应功能，反而被利用以促进肿瘤的生长。NF-kappaB通路在肿瘤环境中的持续激活代表了一种机制，这种机制似乎有利于肿瘤的存活并驱动免疫细胞的无效激活。其结果是肿瘤逃逸宿主免疫系统。肿瘤逃逸是通过激活一种或多种分子机制来实现的，这些机制导致免疫细胞功能的抑制或抗肿瘤效应细胞的凋亡。阻止肿瘤逃逸的能力取决于对肿瘤微环境中运作的细胞和分子通路的更好理解。新兴的治疗策略旨在将有利于肿瘤的微环境改变为有利于急性反应和强效抗肿瘤活性的微环境。

英文摘要 ​

The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions. Although various immune effector cells are recruited to the tumor site, their anti-tumor functions are downregulated, largely in response to tumor-derived signals. Infiltrates of inflammatory cells present in human tumors are chronic in nature and are enriched in regulatory T cells (T(reg)) as well as myeloid suppressor cells (MSC). Immune cells in the tumor microenvironment not only fail to exercise antitumor effector functions, but they are co-opted to promote tumor growth. Sustained activation of the NF-kappaB pathway in the tumor milieu represents one mechanism that appears to favor tumor survival and drive abortive activation of immune cells. The result is tumor escape from the host immune system. Tumor escape is accomplished through the activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells. The ability to block tumor escape depends on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Novel therapeutic strategies that emerge are designed to change the pro-tumor microenvironment to one favoring acute responses and potent anti-tumor activity.

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主要研究问题 ​

  1. 肿瘤微环境如何具体影响免疫细胞的功能和活性？
  2. 在肿瘤微环境中，NF-kappaB通路的持续激活对肿瘤生存的影响有哪些具体机制？
  3. 有哪些新的治疗策略可以有效改变肿瘤微环境，从而增强抗肿瘤免疫反应？
  4. 不同类型的肿瘤微环境对免疫细胞的抑制作用是否存在显著差异？
  5. 如何通过靶向肿瘤微环境中的特定细胞或信号通路来提高现有癌症治疗的效果？

核心洞察 ​

研究背景和目的 ​

肿瘤微环境是由肿瘤细胞及其周围组织构成的复杂生态系统，影响肿瘤的生长和进展。尽管免疫效应细胞被招募至肿瘤部位，但其抗肿瘤功能往往受到抑制。本文旨在探讨肿瘤微环境在促进肿瘤生长中的作用及其对免疫逃逸的影响。

主要方法/材料/实验设计 ​

本研究通过分析肿瘤微环境中细胞类型及其相互作用，阐明了肿瘤如何利用微环境来促进自身生长并逃避免疫监视。研究方法包括：

  • 免疫细胞的功能分析
  • 细胞间信号传导途径的探讨
  • 肿瘤微环境中各种细胞的特征描述

以下是肿瘤微环境的主要组成及其相互作用的流程图：

Mermaid diagram

关键结果和发现 ​

  1. 肿瘤微环境的组成：包括肿瘤细胞、肿瘤基质、血管及多种免疫细胞（如T细胞、巨噬细胞等）。
  2. 免疫细胞功能抑制：肿瘤微环境中的T细胞表现出增殖和细胞毒性降低，调节性T细胞的比例增高，导致抗肿瘤免疫反应的抑制。
  3. NF-κB信号通路：该通路在肿瘤微环境中持续激活，促进肿瘤细胞生存并抑制免疫细胞的效应功能。
  4. 免疫逃逸机制：肿瘤通过多种机制（如下调HLA分子表达、释放抑制性细胞因子等）逃避宿主免疫监视。

主要结论/意义/创新性 ​

肿瘤微环境不仅支持肿瘤的生长，还通过改变免疫细胞的功能促进免疫逃逸。理解这些机制为开发新型肿瘤免疫治疗策略提供了基础，例如，通过改变肿瘤微环境的特征来恢复免疫功能。

研究局限性和未来方向 ​

  1. 研究局限性：本研究主要基于已有文献和实验结果，缺乏新的实验数据支持。
  2. 未来方向：
    • 进一步探索肿瘤微环境中不同细胞的功能及其相互作用。
    • 开发针对肿瘤微环境的治疗策略，改变其对抗肿瘤免疫的抑制作用。
    • 研究如何有效调节调节性T细胞和髓源抑制细胞的功能，以提高免疫治疗的效果。

本研究强调了肿瘤微环境在肿瘤生物学中的重要性，并为未来的治疗策略提供了新的视角。

参考文献 ​

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  5. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. - Tyler J Curiel;George Coukos;Linhua Zou;Xavier Alvarez;Pui Cheng;Peter Mottram;Melina Evdemon-Hogan;Jose R Conejo-Garcia;Lin Zhang;Matthew Burow;Yun Zhu;Shuang Wei;Ilona Kryczek;Ben Daniel;Alan Gordon;Leann Myers;Andrew Lackner;Mary L Disis;Keith L Knutson;Lieping Chen;Weiping Zou - Nature medicine (2004)
  6. Fatal attraction: tumors beckon regulatory T cells. - Ethan M Shevach - Nature medicine (2004)
  7. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. - Eli Pikarsky;Rinnat M Porat;Ilan Stein;Rinat Abramovitch;Sharon Amit;Shafika Kasem;Elena Gutkovich-Pyest;Simcha Urieli-Shoval;Eithan Galun;Yinon Ben-Neriah - Nature (2004)
  8. Cancer: an inflammatory link. - Fran Balkwill;Lisa M Coussens - Nature (2004)
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  1. Immunosenescence and cancer vaccines. - Mauro Provinciali - Cancer immunology, immunotherapy : CII (2009)
  2. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. - Eilon D Kirson;Moshe Giladi;Zoya Gurvich;Aviran Itzhaki;Daniel Mordechovich;Rosa S Schneiderman;Yoram Wasserman;Bernhard Ryffel;Dorit Goldsher;Yoram Palti - Clinical & experimental metastasis (2009)
  3. Stromal cell expression of caveolin-1 predicts outcome in breast cancer. - Erica K Sloan;Daniel R Ciocca;Normand Pouliot;Anthony Natoli;Christina Restall;Michael A Henderson;Mariel A Fanelli;Fernando D Cuello-Carrión;Francisco E Gago;Robin L Anderson - The American journal of pathology (2009)
  4. B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. - Judith Leitner;Christoph Klauser;Winfried F Pickl;Johannes Stöckl;Otto Majdic;Anaïs F Bardet;David P Kreil;Chen Dong;Tomohide Yamazaki;Gerhard Zlabinger;Katharina Pfistershammer;Peter Steinberger - European journal of immunology (2009)
  5. Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. - Geetha Srikrishna;Hudson H Freeze - Neoplasia (New York, N.Y.) (2009)
  6. Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells. - Ryan A Wilcox;David A Wada;Steven C Ziesmer;Sherine F Elsawa;Nneka I Comfere;Allan B Dietz;Anne J Novak;Thomas E Witzig;Andrew L Feldman;Mark R Pittelkow;Stephen M Ansell - Blood (2009)
  7. Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment. - Yusuke Sato;Yasufumi Goto;Norihiko Narita;Dave S B Hoon - Cancer microenvironment : official journal of the International Cancer Microenvironment Society (2009)
  8. Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+ B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma. - Dominik Pretscher;Luitpold V Distel;Gerhard G Grabenbauer;Michael Wittlinger;Maike Buettner;Gerald Niedobitek - BMC cancer (2009)
  9. The tumor microenvironment: the making of a paradigm. - Isaac P Witz - Cancer microenvironment : official journal of the International Cancer Microenvironment Society (2009)
  10. Prognostic and therapeutic potential of nuclear receptors in head and neck squamous cell carcinomas. - Shirley K Knauer - Journal of oncology (2009)

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