Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands.
TECObiosciences GmbH, Landshut, Germany.
Gut. 2020 Apr;69(4):691-703. doi: 10.1136/gutjnl-2019-318672. Epub 2019 Jul 3.
A comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC.
Thirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence.
We discovered that a previously unappreciated innate lymphocyte population (LinCD7CD127CD56CD45RO) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103CD69) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DRCD38PD-1) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes.
This work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.
全面了解抗癌免疫反应对于癌症免疫疗法的最佳应用和发展至关重要。我们通过高维分析揭示了结直肠癌（CRC）患者的局部和全身免疫谱，为 CRC 的免疫结构提供了无偏倚的特征描述。
通过质谱细胞术在 35 个 CRC 组织、26 个肿瘤相关淋巴结、17 个结直肠健康黏膜和 31 名 CRC 患者的 19 个外周血样本中同时评估 36 个免疫细胞标志物的单细胞水平。此外，通过流式细胞术、单细胞 RNA 测序和多光谱免疫荧光进行肿瘤浸润淋巴细胞的功能、转录和空间分析。
我们发现，一个以前未被重视的固有淋巴细胞群体（LinCD7CD127CD56CD45RO）在 CRC 组织中富集，并表现出细胞毒性活性。该亚群表现出组织驻留（CD103CD69）表型，在免疫原性错配修复（MMR）缺陷的 CRC 中最为丰富。其在肿瘤中的存在与肿瘤驻留细胞毒性、辅助和 γδ T 细胞的浸润相关，具有高度相似的激活（HLA-DRCD38PD-1）表型。值得注意的是，激活的 γδ T 细胞几乎只存在于 MMR 缺陷的癌症中。肿瘤驻留细胞毒性和 γδ T 细胞的非激活对应物存在于 CRC 和健康黏膜组织中，但不存在于淋巴结中，除了肿瘤阳性淋巴结。
这项工作为理解 CRC 异质性和复杂的免疫景观提供了蓝图，包括鉴定以前未被重视的免疫细胞亚群。肿瘤驻留固有和适应性免疫细胞群体的同时存在表明，在治疗环境中可以靶向利用它们的抗肿瘤特性。
Zotero 插件