Single-Cell Immune Mapping of Melanoma Sentinel Lymph Nodes Reveals an Actionable Immunotolerant Microenvironment.
Single-Cell Immune Mapping of Melanoma Sentinel Lymph Nodes Reveals an Actionable Immunotolerant Microenvironment.
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DOI：
10.1158/1078-0432.ccr-21-0664
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发表时间：
2022-05-13
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提高我们对原发性肿瘤前哨淋巴结（SLN）内癌细胞免疫反应的理解，有望确定新的方法来刺激临床上有意义的癌症免疫。我们使用飞行时间质谱（CyTOF）、流式细胞术和T细胞受体免疫测序对黑色素瘤患者前哨淋巴结中的免疫细胞进行同步单细胞分析。我们发现相对于非黑色素瘤SLN，在黑色素瘤SLN中选择性地增加效应记忆α β T细胞、TCR克隆性和γ δ T细胞，这与抗肿瘤免疫应答的可能激活一致。然而，我们还观察到在携带黑色素瘤的SLN中存在明显的免疫耐受性环境，其表现为NK细胞减少和受损以及CD8 + CD57 + PD-1+细胞水平增加，已知其显示低黑色素瘤杀伤能力。与未携带黑素瘤的SLN相比，在携带黑素瘤的SLN中观察到的其他变化包括：（i）降低的⑶ 8 + ⑶ 69 + T细胞/T调节细胞比率;（ii）⑶ 4+和⑶ 8 + T细胞上的高PD-1表达;和（iii）γ δ T细胞上的高CTLA-4表达。我们的数据表明，这些免疫学变化损害抗黑色素瘤免疫力，并有助于高复发率。我们建议开展临床试验，以测试III期黑色素瘤患者在SLN切除术前新辅助施用抗PD-1抗体。在这篇文章中，我们描述了一种多尺度免疫分析策略的发展，以绘制前哨淋巴结（SLN）的免疫景观，以寻找肿瘤驱动的免疫变化，从而指导早期黑色素瘤患者设计新的免疫治疗策略。为了表征黑色素瘤SLN的免疫微环境，我们分析了来自100多名诊断为原发性临床I/II期和III期皮肤黑色素瘤患者的样本。使用质谱仪、流式细胞术和T细胞受体免疫测序对免疫细胞进行同步单细胞分析，我们鉴定了独特的肿瘤驱动的T、NK和先天免疫细胞特征，这些特征存在于III期携带黑色素瘤的前哨淋巴结中，但在I/II期非携带黑色素瘤的前哨淋巴结中不存在。
Improving our understanding of the immunological response to cancer cells within the sentinel lymph nodes (SLNs) of primary tumors is expected to identify new approaches to stimulate clinically meaningful cancer immunity. We used mass cytometry by time-of-flight (CyTOF), flow cytometry, and T cell receptor immunosequencing to conduct simultaneous single-cell analyses of immune cells in the SLNs of melanoma patients. We found increased effector-memory αβ T cells, TCR clonality, and γδ T cells selectively in the melanoma-bearing SLNs relative to non-melanoma-bearing SLNs, consistent with possible activation of an anti-tumor immune response. However, we also observed a markedly immunotolerant environment in the melanoma-bearing SLNs indicated by reduced and impaired NK cells and increased levels of CD8+CD57+PD-1+ cells which are known to display low melanoma killing capabilities. Other changes observed in melanoma-bearing SLNs when compared to non-melanoma bearing SLNs include: (i) reduced CD8+CD69+ T cells/T regulatory cells ratio; (ii) high PD-1 expression on CD4+ and CD8+ T cells; and (iii) high CTLA-4 expression on γδ T cells. Our data suggests that these immunological changes compromise anti-melanoma immunity and contribute to a high relapse rate. We propose the development of clinical trials to test the neo-adjuvant administration of anti-PD-1 antibodies prior to SLN resection in stage III melanoma patients. In this article, we describe the development of a multiscale immune profiling strategy to map the immune landscape of sentinel lymph nodes (SLN) in our search for tumor-driven immune changes that can guide the design of novel immunotherapeutic strategies for patients with early-stage melanoma. To characterize the immune microenvironment of melanoma SLNs, we analyzed samples from over 100 patients diagnosed with a primary clinical stage I/II and III cutaneous melanoma. Using mass cytometry, flow cytometry, and T cell receptor immunosequencing to conduct simultaneous single-cell analyses of immune cells, we identified unique tumor-driven T, NK, and innate immune cell signatures that are present in stage III melanoma-bearing SLNs, but absent in stage I/II non-melanoma-bearing SLNs.