《细胞》：肿瘤中发现隐藏的免疫细胞“组织”

资讯来源：Broad Institute of MIT and Harvard

编辑翻译：奇奇

本文献于2021年9月1日发表在国际著名医学期刊《细胞》（Cell）上。文中来自麻省理工学院和哈佛大学的研究人员在肿瘤中发现了之前未曾观察到的免疫细胞空间组织，这为肿瘤治疗提供了新思路。

研究人员发现，人类部分结直肠肿瘤中的免疫细胞聚集在一起，就像士兵在列队作战一样。通过使用单细胞分析和成像技术的独特组合，以及新开发的数据分析方法，科学家们发现了以前在肿瘤中未观察到的细胞空间组织水平。

激活的和潜在的肿瘤反应性T细胞（白色、绿色和洋红色）、恶性细胞（蓝色）、免疫细胞的分子（黄色）。

发表在《细胞》杂志上的研究结果指出，在某些类型的结直肠肿瘤中，相互作用的免疫细胞网络更容易被免疫系统“发现”。这表明含有这些中枢的癌症可能会对称为免疫疗法的癌症药物产生反应，这种药物会刺激免疫系统杀死癌细胞。来自麻省理工学院和哈佛大学布罗德研究所、麻省理工学院麻省总医院、布列根和妇女医院和哈佛医学院免疫疾病中心以及丹娜法伯癌症研究院的科学家们表示，这项研究可能会为如何让其他肿瘤对此类治疗更加敏感提供启发。

布罗德研究所细胞回路项目的联合主任、该研究的资深合著者Nir Hacohen说：“通过分析肿瘤中每个细胞的活动，我们能够监听细胞之间的对话，并分辨出一个以前我们看不见的组织。”他也是麻省总医院癌症免疫学中心主任和哈佛医学院教授。

其他资深作者包括Ana Anderson（布罗德研究所成员、哈佛医学院副教授、布莱根妇女医院科学家以及免疫疾病中心核心教员）、 Aviv Regev（该研究项目最初的核心成员）、Orit Rozenblatt-Rosen（研究期间布罗德克拉曼细胞天文台的单细胞基因组学高级主任）。

科学家们在不同的细胞类型中寻找相互协调的基因程序，当一个基因程序的表达上升或下降时，另一个程序也会随之改变。

研究人员说：“我们意识到，了解肿瘤的单个部分和细胞类型并不能告诉我们整个事件，我们需要了解每个细胞在做什么，以及细胞如何相互协作来完成它们的任务。”

分析显示，恶性肿瘤细胞和两种类型的免疫细胞（T细胞和骨髓细胞）能相互作用并启动特定的基因程序。为了了解表达这些基因程序的细胞是如何在肿瘤内部组织起来的，研究小组在显微镜下分析了来自患者的肿瘤样本，重点研究了具有协调基因程序的T细胞和癌细胞之间的相互作用。这使得他们能够锁定肿瘤深处的免疫细胞集束中心。

观察不同细胞类型的共变程序为这个复杂的肿瘤生态系统提供了一个新的视角。科学家们还注意到，与MMRp肿瘤相比，MMRd肿瘤(对免疫治疗反应更好)中中枢细胞的发生率更高。他们假设中枢可能与肿瘤对治疗的反应有关。

“事实证明，这些肿瘤的免疫是相当有组织的，而不是扩散的，”Chen博士说，“特别是当我们观察MMRd肿瘤时，这些清楚的结构包含了活跃的免疫细胞。”

研究小组目前正计划进行研究，使用相同的方法跟踪结直肠癌中的免疫细胞如何在免疫治疗过程中改变它们的基因表达模式和彼此之间的交流。Rozenblatt-Rosen说：“我们希望这项研究能为未来研究癌症细胞间的组织提供一个框架。”

英文原文

Immune Cell ‘hubs’ Discovered Hiding in Tumors

A team of researchers have discovered that immune cells in some human colorectal tumors gather together in clusters, like soldiers mobilizing in formation. By using a unique combination of single-cell profiling and imaging technologies, along with newly developed data analysis approaches, the scientists found a level of spatial organization of cells not observed before in tumors.

The findings, published in Cell, point to networks of interacting immune cells in certain types of colorectal tumors that tend to be more readily “seen” by the immune system. This suggests that cancers containing these hubs may be more likely to respond to cancer drugs called immunotherapies, which spur the immune system to kill cancer cells. The scientists, from the Broad Institute of MIT and Harvard, Massachusetts General Hospital, MIT, the Evergrande Center for Immunologic Diseases at Brigham and Women's Hospital and Harvard Medical School, and Dana-Farber Cancer Institute, say the study could shed light on how to make other tumors more responsive to such treatments.

“By analyzing the activities of each cell in the tumor, we were able to listen in to the dialogue between cells and discern an organization that was previously invisible to us,” said Nir Hacohen, co-senior author of the study, co-director of the Broad Institute's Cell Circuits Program, director of the Center for Cancer Immunology at Massachusetts General Hospital, and a professor at Harvard Medical School.

Other co-senior authors are Ana Anderson, institute member at Broad, an associate professor at Harvard Medical School, ascientist at Brigham and Women's Hospital, and a core faculty member of the Evergrande Center for Immunologic Diseases；Aviv Regev, who was a coreinstitute member at Broad when the study began；and Orit Rozenblatt-Rosen, who was senior director of single cell genomics at the Klarman Cell Observatory at Broad during the study.

The scientists searched for gene programs that are coordinated with each other across disparate cell types—when the expression of one gene program went up or down, another program would also change in concert.

“We realized that understanding the individual parts of the tumors and the cell types doesn't tell us the whole story,” researchers said. “We need to understand what each cell is doing and how the cells work together with each other to accomplish their tasks.”

The analysis revealed that malignant tumor cells and two types of immune cells—T cells and myeloid cells—were likely interacting with each other and turning on specific gene programs. To see how the cells expressing these gene programs might be organized inside tumors, the team analyzed tumor samples from patients under the microscope, focusing on interactions between the T cells with the coordinated gene programs and the cancer cells. This allowed them to zero in on the clustered hubs of immune cells deep inside tumors.

Looking at co-varying programs in different cell types provided a fresh view of this complex tumor ecosystem. The scientists also noticed a higher occurrence of the hubs in MMRd tumors (which respond better to immunotherapies) compared to MMRp tumors. They hypothesize that the hubs might be involved in how tumors respond to treatment.

“It turns out that the immunology of these tumors is quite organized rather than being diffuse throughout,” Chen said. “Particularly when we looked at MMRd tumors, there were these clear structures containing the active immune cells.”

The research team is now planning studies that use the same approaches to track how immune cells in colorectal tumors change their gene expression patterns and communication with each other during treatment with immunotherapy. “We hope this study provides a framework for future studies that interrogate inter-cellular organization in cancer,” Rozenblatt-Rosen said.

参考文献 

Karin Pelka et al, Spatially organized multicellular immune hubs in human colorectal cancer, Cell (2021).

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