研究揭示免疫功能紊乱与进展期肾细胞癌的关系
2021-03-15   阅读:471   来源:细胞

美国丹娜-法伯癌症研究所Catherine J. Wu研究小组取得一项新突破。他们的最新研究揭示了免疫功能紊乱与进展期肾细胞癌的关系。相关论文在线发表在2021年3月11日出版的《癌细胞》杂志上。

研究人员对来自透明细胞肾细胞癌(ccRCC)患者不同疾病阶段(早期、局部晚期和晚期/转移性)的164,722个肿瘤和癌旁非肿瘤组织单细胞进行了单细胞RNA和T细胞受体测序。转移性癌症富含最终耗竭CD8T细胞,其限制了T细胞受体的多样性。

在骨髓腔室内,促炎性巨噬细胞减少,而晚期疾病中抑制性M2巨噬细胞增加。在晚期肿瘤中同时出现末端耗竭CD8+T细胞和M2巨噬细胞,并表达造成T细胞功能障碍和M2极化的配体和受体。该免疫功能障碍回路与个体预后较差有关,并揭示了ccRCC中潜在的可靶向免疫抑制途径。

科学家揭示,肿瘤免疫微环境在ccRCC的癌症进展和免疫治疗反应中起着至关重要的作用,但尚不清楚该肿瘤微环境中免疫细胞的组成和表型状态。

附:英文原文

Title: Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

Author: David A. Braun, Kelly Street, Kelly P. Burke, David L. Cookmeyer, Thomas Denize, Christina B. Pedersen, Satyen H. Gohil, Nicholas Schindler, Lucas Pomerance, Laure Hirsch, Ziad Bakouny, Yue Hou, Juliet Forman, Teddy Huang, Shuqiang Li, Ang Cui, Derin B. Keskin, John Steinharter, Gabrielle Bouchard, Maxine Sun, Erica M. Pimenta, Wenxin Xu, Kathleen M. Mahoney, Bradley A. McGregor, Michelle S. Hirsch, Steven L. Chang, Kenneth J. Livak, David F. McDermott, Sachet A. Shukla, Lars R. Olsen, Sabina Signoretti, Arlene H. Sharpe, Rafael A. Irizarry, Toni K. Choueiri, Catherine J. Wu

Issue&Volume: 2021-03-11

Abstract: The tumor immune microenvironment plays a critical role in cancer progression andresponse to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the compositionand phenotypic states of immune cells in this tumor are incompletely characterized.We performed single-cell RNA and T cell receptor sequencing on 164,722 individualcells from tumor and adjacent non-tumor tissue in patients with ccRCC across diseasestages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8+ T cells were enriched in metastatic disease and were restricted in T cell receptordiversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased,and suppressive M2-like macrophages were increased in advanced disease. Terminallyexhausted CD8+ T cells and M2-like macrophages co-occurred in advanced disease and expressed ligandsand receptors that support T cell dysfunction and M2-like polarization. This immunedysfunction circuit is associated with a worse prognosis in external cohorts and identifiespotentially targetable immune inhibitory pathways in ccRCC.

DOI: 10.1016/j.ccell.2021.02.013

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