Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Neoplasia. 2024 Dec;58:101072. doi: 10.1016/j.neo.2024.101072. Epub 2024 Oct 24.
Gamma delta T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin-17 (IL-17) within the tumor microenvironment of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including poised effector-like T cells, tissue-resident memory T cells, progenitor exhausted-like T cells, and exhausted T cells, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. We proposed anti-tumor γδ T effector cells may arise from tissue-resident progenitor cells based on the trajectory analysis. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology.
γδ T 细胞由于其细胞毒性特性，在抗肿瘤免疫中发挥着至关重要的作用。然而，γδ T 细胞在结直肠癌（CRC）肿瘤微环境中产生促肿瘤生成的白细胞介素-17（IL-17）的作用和程度仍存在争议。在这项研究中，我们重新分析了 9 个人类 CRC 全组织单细胞 RNA 测序数据集，在 165 名 CRC 患者的肿瘤或相邻正常组织中，从 951785 个总细胞中鉴定出 18483 个 γδ T 细胞。我们的结果证实，肿瘤浸润 γδ T 细胞在肿瘤和相邻正常组织中均表现出高细胞毒性相关转录，但至关重要的是，没有任何 γδ T 细胞簇显示出产生 IL-17 的潜力。我们还鉴定了各种 γδ T 细胞亚群，包括有潜力的效应样 T 细胞、组织驻留记忆 T 细胞、祖细胞耗竭样 T 细胞和耗竭 T 细胞，并注意到与正常组织相比，肿瘤浸润 γδ T 细胞中细胞毒性分子的表达增加。我们根据轨迹分析提出，抗肿瘤 γδ T 效应细胞可能来源于组织驻留祖细胞。我们的工作表明，CRC 中的 γδ T 细胞主要作为细胞毒性效应细胞发挥作用，而不是产生 IL-17，减轻了它们在 CRC 中潜在促肿瘤作用的担忧，突出了准确描述这些细胞在癌症免疫治疗研究中的重要性，以及在癌症免疫学研究中不可忽视的小鼠和人类免疫系统之间的跨物种差异。
