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Organoid Models of Tumor Immunology. ​

文献信息 ​

DOI10.1016/j.it.2020.06.010
PMID32654925
期刊Trends in immunology
影响因子13.9
JCR 分区Q1
发表年份2020
被引次数217
关键词免疫疗法, 类器官, 肿瘤微环境
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN1471-4906
页码652-664
期号41(8)
作者Kanako Yuki, Ning Cheng, Michitaka Nakano, Calvin J Kuo

一句话小结 ​

本研究探讨了肿瘤微环境中细胞相互作用对癌症进展和免疫治疗反应的影响，强调了三维类器官培养技术在模拟患者特异性肿瘤-免疫相互作用中的应用潜力。通过引入肿瘤类器官，研究为免疫肿瘤学、免疫疗法建模和精准医学的转化应用提供了新的方向和方法。

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免疫疗法 · 类器官 · 肿瘤微环境

摘要 ​

肿瘤微环境（TME）中的细胞相互作用显著影响癌症进展和药物反应。临床免疫疗法的有效性引发了对肿瘤免疫微环境的指数级关注，这反过来又催生了对强大实验系统的迫切需求，以模拟患者特异性的肿瘤-免疫相互作用。传统的二维体外肿瘤免疫治疗模型通常将不朽的癌细胞系与免疫成分重组，这些成分往往来自外周血。然而，最近开发的三维体外类器官培养方法现在允许常规培养人类肿瘤活检，并越来越多地融入免疫成分。在此，我们提出了对近期进展的观点，并建议将肿瘤类器官应用于免疫肿瘤学研究、免疫疗法建模和精准医学中的转化应用。

英文摘要 ​

Cellular interactions in the tumor microenvironment (TME) significantly govern cancer progression and drug response. The efficacy of clinical immunotherapies has fostered an exponential interest in the tumor immune microenvironment, which in turn has engendered a pressing need for robust experimental systems modeling patient-specific tumor-immune interactions. Traditional 2D in vitro tumor immunotherapy models have reconstituted immortalized cancer cell lines with immune components, often from peripheral blood. However, newly developed 3D in vitro organoid culture methods now allow the routine culture of primary human tumor biopsies and increasingly incorporate immune components. Here, we present a viewpoint on recent advances, and propose translational applications of tumor organoids for immuno-oncology research, immunotherapy modeling, and precision medicine.

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主要研究问题 ​

  1. 在肿瘤免疫微环境中，器官oid模型如何模拟患者特异性的免疫反应？
  2. 3D器官oid培养方法相较于传统2D模型在研究肿瘤免疫学方面的优势是什么？
  3. 目前有哪些成功的临床应用案例展示了器官oid在免疫疗法中的作用？
  4. 如何评估器官oid模型在药物反应预测中的有效性和可靠性？
  5. 未来器官oid模型在个性化医疗和精准医学中的潜在发展方向是什么？

核心洞察 ​

研究背景和目的 ​

肿瘤微环境（TME）中的细胞相互作用显著影响癌症的进展和药物反应。临床免疫疗法的有效性激发了对肿瘤免疫微环境的浓厚兴趣，亟需建立强大的实验系统以模拟患者特异性的肿瘤-免疫相互作用。传统的二维（2D）体外模型不足以真实再现人类肿瘤的复杂免疫生物学，而新开发的三维（3D）类器官培养方法能够定期培养人类肿瘤活检样本，并逐步整合免疫成分。

主要方法/材料/实验设计 ​

本研究采用多种3D类器官培养系统以模拟肿瘤免疫微环境，包括：

  • 沉浸式Matrigel培养：将肿瘤细胞在Matrigel中培养，添加生长因子以促进细胞自我更新和分化。
  • 微流体3D培养：在微流体装置中培养肿瘤球体，允许肿瘤细胞和免疫细胞的相互作用。
  • 气-液界面（ALI）培养：将肿瘤组织碎片嵌入胶原中，顶部暴露于空气，允许细胞获得足够的氧气。
Mermaid diagram

关键结果和发现 ​

  1. 沉浸式Matrigel培养仅能富集上皮肿瘤细胞，缺乏基质成分。
  2. 微流体培养能够保持肿瘤细胞和自体免疫细胞的相互作用，适用于短期研究。
  3. ALI培养保留了肿瘤的遗传变异和复杂的细胞组成，能够长时间维持细胞活性。

主要结论/意义/创新性 ​

研究表明，3D类器官培养系统为研究肿瘤免疫微环境提供了新的平台，能够模拟肿瘤-免疫细胞相互作用，推动免疫疗法的开发。通过这些系统，可以更好地理解肿瘤免疫学及其在个性化医学中的应用潜力。

研究局限性和未来方向 ​

  1. 局限性：当前模型在维持免疫细胞的长期存活和功能方面仍面临挑战，且在重建免疫微环境时，单一免疫细胞类型的加入可能无法全面再现复杂的细胞相互作用。
  2. 未来方向：需开发更复杂的类器官系统以整合多种免疫细胞，并验证其在临床反应中的预测能力。探索与病原体或共生微生物的相互作用，以进一步理解癌症相关炎症及其治疗潜力。

通过这些研究，类器官技术有望为肿瘤免疫治疗的基础科学和临床转化提供重要支持。

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引用本文的文献 ​

  1. Targeting TANK-binding kinase 1 (TBK1) in cancer. - Or-Yam Revach;Shuming Liu;Russell W Jenkins - Expert opinion on therapeutic targets (2020)
  2. Exploration of Feasible Immune Biomarkers for Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma Treatment in Real World Clinical Practice. - Hui-Ching Wang;Tsung-Jang Yeh;Leong-Perng Chan;Chin-Mu Hsu;Shih-Feng Cho - International journal of molecular sciences (2020)
  3. The future of microfluidics in immune checkpoint blockade. - Jonathan Briones;Wilfred Espulgar;Shohei Koyama;Hyota Takamatsu;Eiichi Tamiya;Masato Saito - Cancer gene therapy (2021)
  4. Targeting metastatic cancer. - Karuna Ganesh;Joan Massagué - Nature medicine (2021)
  5. Bioinformatic Approaches to Validation and Functional Analysis of 3D Lung Cancer Models. - P Jonathan Li;Jeroen P Roose;David M Jablons;Johannes R Kratz - Cancers (2021)
  6. An expanded universe of cancer targets. - William C Hahn;Joel S Bader;Theodore P Braun;Andrea Califano;Paul A Clemons;Brian J Druker;Andrew J Ewald;Haian Fu;Subhashini Jagu;Christopher J Kemp;William Kim;Calvin J Kuo;Michael McManus;Gordon B Mills;Xiulei Mo;Nidhi Sahni;Stuart L Schreiber;Jessica A Talamas;Pablo Tamayo;Jeffrey W Tyner;Bridget K Wagner;William A Weiss;Daniela S Gerhard; - Cell (2021)
  7. Patient-Derived Organoids for Precision Cancer Immunotherapy. - Mikaela Grönholm;Michaela Feodoroff;Gabriella Antignani;Beatriz Martins;Firas Hamdan;Vincenzo Cerullo - Cancer research (2021)
  8. Recent advances in preclinical models for lung squamous cell carcinoma. - Yuanwang Pan;Han Han;Kristen E Labbe;Hua Zhang;Kwok-Kin Wong - Oncogene (2021)
  9. The Role of Network Science in Glioblastoma. - Marta B Lopes;Eduarda P Martins;Susana Vinga;Bruno M Costa - Cancers (2021)
  10. Patient-Derived Organoids as a Model for Cancer Drug Discovery. - Colin Rae;Francesco Amato;Chiara Braconi - International journal of molecular sciences (2021)

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