摘要：2024年第九届国际干细胞论坛（IFSC）聚焦于干细胞基础研究、再生医学、细胞治疗以及临床研究指南的应用，汇集了来自世界各地的专家学者，共同探讨科学发现和技术进步的最新前沿。会议期间，《血液时讯》特邀剑桥大学Simón Méndez-Ferrer教授从微环境调

2024年第九届国际干细胞论坛（IFSC）聚焦于干细胞基础研究、再生医学、细胞治疗以及临床研究指南的应用，汇集了来自世界各地的专家学者，共同探讨科学发现和技术进步的最新前沿。会议期间，《血液时讯》特邀剑桥大学Simón Méndez-Ferrer教授从微环境调节角度分享改善髓系恶性肿瘤治疗的关键路径。现将精粹整理成文，以飨读者。

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《血液时讯》：髓系恶性肿瘤是造血干细胞或祖细胞的克隆性疾病。您能否谈谈骨髓微环境中的细胞如何影响这些疾病的进展，以及我们如何利用这一知识来改善治疗策略？

Simón Méndez-Ferrer教授：实际上，当科研人员开始专注于骨髓微环境这一新的研究视角时，情况变得格外引人关注。血液病的根源可能并非直接源自突变细胞本身，而是微环境细胞在其中的潜在作用，特别是它们是否对非造血细胞产生了影响，进而诱发了一系列变化。这些变化的形式多种多样，其中在血液系统恶性肿瘤伴随生殖系突变的情况下，会涉及突变分子的表达；而在其他情况下，则仅表现为非造血细胞内的变化。

尤为值得注意的是，在多数相关实验中，所构建的小鼠模型竟罹患了一种与骨髓增殖性肿瘤相似的疾病，这一发现强烈暗示非造血细胞在推动这些疾病的发展进程中扮演了关键角色，这一观察结果可追溯至多年前。随后，科研人员进一步深入探究，试图明确在众多细胞中，哪些细胞可能发挥着更为重要的作用，并据此发现了一些有力证据，表明造血微环境有可能成为诱导这些恶性肿瘤发展的致癌因素。然而，关于微环境作用机制的大部分证据，实际上源于造血细胞的突变，这些突变导致微环境发生异常变化，使其无法有效支持正常的造血功能，反而促进了恶性肿瘤的滋生与发展。

因此，微环境的这种病理性改变可能历经多年才逐渐显现。值得注意的是，部分突变甚至在个体出生前就已存在。然而，患者往往直至老年阶段才表现出与这些突变相关的疾病症状。这显然表明，在宏观环境的漫长岁月中，可能发生了诸多事件，共同促成了疾病的发生与发展。故鉴于当前已能够实现对这类疾病的早期检测，我们就有了采取干预措施、预防宏观环境损伤的机会，进而有望阻断疾病的进展或对已发生的疾病进行有效治疗。

Hematology Frontier：Myeloid malignancies are clonal disorders of the progenitor cells or hematopoietic stem cells. Could you discuss how cells in the bone marrow microenvironment influence the progression of these diseases and how we can use this knowledge to improve treatment strategies?

Professor Simón Méndez-Ferrer：So actually, it was quite striking when people started examining the possibility that the cells that are not the mutant cells responsible for hematological diseases, but rather, the microenvironmental cells, might play a role in generating alterations in non-hematopoietic cells. These alterations were of different types, expressing molecules that were mutated in the case of germline mutations during hematological malignancies. But in other cases, they simply represented alterations in non-hematopoietic cells. And it was striking that in most of these experiments, the mouse models developed a type of disease that resembled myeloproliferative neoplasms. This suggests an important role for non-hematopoietic cells in the development of these diseases. This observation was made many years ago. Subsequently, researchers began to investigate which cells might be more important compared to others and found evidence that the niche could be an oncogenic inducer for the development of these malignancies.

However, most of the evidence for the role of the microenvironment actually stems from the consequences of mutations in hematopoietic cells, whereby the microenvironment becomes altered and stops functioning properly to support hematopoiesis, instead promoting the development of malignancy.

The alteration of the microenvironment can develop over many years. Some of these mutations are now detectable even before birth. Yet, patients typically manifest the disease associated with aging. Clearly, many factors are involved in the overall environment over the years that may contribute to the onset and progression of the disease. Therefore, now that this disease can be detected quite early, there is an opportunity for intervention and prevention of damage to the microenvironment, which may impede disease progression or enhance treatment effectiveness once the disease has developed.

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《血液时讯》：您在剑桥大学的团队正在研究如何通过调节微环境来改善髓系恶性肿瘤的治疗。在您的研究中，有哪些关键发现可能为开发新的治疗策略提供线索？

Simón Méndez-Ferrer教授：一项引人注目的发现揭示，造血微环境已经失去了对驱动这些疾病进程的突变克隆扩增的有效控制能力。实际上，在诸如骨髓增殖性肿瘤等疾病中，我们观察到疾病的表现形式具有多样性，其扩展或突变克隆的增殖程度各不相同，并且在某些情况下，可能会进一步恶化，对患者的健康状况构成更大的威胁。

这种疾病的异质性同样与特定微环境之间复杂多样的相互作用密切相关。我们已经鉴别出了一系列参与这些相互作用的分子，并认为这些分子有望成为干预的新靶点，旨在恢复造血细胞与其造血微环境之间的正常交互作用，并有效预防异常状况的发生。例如，防止造血细胞从原本能够调控干细胞扩增的微环境中脱离出来，进而迁移到更有利于突变克隆自由扩增的微环境中。

因此，我认为这一发现为临床干预提供了一个极具潜力的新机会，有望成为靶向突变克隆治疗的重要辅助手段。

Hematology Frontier：Your team at the University of Cambridge is researching how to improve the treatment of myeloid malignancies by modulating the microenvironment. What key findings in your research could provide clues for developing new treatment strategies?

Professor Simón Méndez-Ferrer：So the most interesting findings suggest that the niche has limited capacity to control the expansion of the mutant clone that is driving these diseases.

And actually, we found that in disorders such as myeloproliferative neoplasm, where there is a variety of manifestations and with different levels of disease expansion or mutant clone expansion, leading to a transformation into a more dangerous situation for the patient.

This heterogeneity is also related to the different interactions with particular microenvironments. We have identified certain molecules that are involved in these interactions, and we think we could target those to restore the normal interactions of hematopoietic stem cells with their niche and prevent the abnormal detachment from a niche that effectively controls stem cell expansion. Instead, they relocate to a permissive environment where the mutant clone can expand more freely. So I think that's an exciting opportunity for intervention, potentially complementing the actual targeting of the mutant clone.

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《血液时讯》：您如何看待免疫、靶向治疗在髓系恶性肿瘤治疗中的潜力，特别是在考虑到微环境调控的情况下？是否有特定的细胞类型或策略在您的研究中显示出特别的前景？

Simón Méndez-Ferrer教授：关于微环境的研究正经历着一场复兴，其中也包括了对免疫微环境的深入探讨，而免疫微环境以往主要是在实体瘤的研究范畴内被考察。然而，如今造血细胞的免疫微环境也受到了极大的关注，因为这些免疫调节机制显然通过与微环境的相互作用而发生了改变。

在研发免疫疗法的过程中，我们必须确保不会遭遇免疫抑制性微环境，否则这些疗法可能难以发挥预期疗效，细胞也无法充分发挥其功能。此外，巨噬细胞在清除突变细胞的过程中扮演着有趣的调节角色，不仅适应性免疫系统参与其中，先天性免疫系统也发挥着至关重要的作用。微环境可能表现出免疫抑制性或免疫刺激性，从而可能影响对免疫疗法的应答。因此，我认为这是一个极具研究价值的领域。

Hematology Frontier：How do you view the potential of immunotherapy and targeted therapy in the treatment of myeloid malignancies, especially considering microenvironmental regulation? Are there specific cell types or strategies that show particular promise in your research?

Professor Simón Méndez-Ferrer：There is a revival in the research around the microenvironment. This is also encompassing the immune microenvironment that has been studied mostly in the context of solid tumors.

But now there is a huge interest also in the immune microenvironment for hematopoietic cells, because it is clear that these immune mechanisms are also modified through interaction with the microenvironment. When you come up with an immunotherapy, you need to make sure that you don't encounter an immune-suppressive microenvironment that will hinder the effectiveness of the treatment. Cells should work as efficiently as expected. Also, there is interesting regulation through the macrophages that are involved in the clearance of mutant cells. Not only the adaptive immune system, but also the innate immune system is very important in this context. And the microenvironment, depending on whether it is immunosuppressive or stimulatory, may participate in the response to this immunotherapy. So I think this is an important area.

来源：肿瘤瞭望