Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
J Immunother Cancer. 2023 Feb;11(2). doi: 10.1136/jitc-2022-005545.
Immunotherapy has revolutionized clinical outcomes for patients suffering from lung cancer, yet relatively few patients sustain long-term durable responses. Recent studies have demonstrated that the tumor immune microenvironment fosters tumorous heterogeneity and mediates both disease progression and response to immune checkpoint inhibitors (ICI). As such, there is an unmet need to elucidate the spatially defined single-cell landscape of the lung cancer microenvironment to understand the mechanisms of disease progression and identify biomarkers of response to ICI.
Here, in this study, we applied imaging mass cytometry to characterize the tumor and immunological landscape of immunotherapy response in non-small cell lung cancer by describing activated cell states, cellular interactions and neighborhoods associated with improved efficacy. We functionally validated our findings using preclinical mouse models of cancer treated with anti-programmed cell death protein-1 (PD-1) immune checkpoint blockade.
We resolved 114,524 single cells in 27 patients treated with ICI, enabling spatial resolution of immune lineages and activation states with distinct clinical outcomes. We demonstrated that CXCL13 expression is associated with ICI efficacy in patients, and that recombinant CXCL13 potentiates anti-PD-1 response in vivo in association with increased antigen experienced T cell subsets and reduced CCR2+ monocytes.
Our results provide a high-resolution molecular resource and illustrate the importance of major immune lineages as well as their functional substates in understanding the role of the tumor immune microenvironment in response to ICIs.
免疫疗法彻底改变了肺癌患者的临床预后，但只有相对较少的患者能获得长期持久的缓解。最近的研究表明，肿瘤免疫微环境促进了肿瘤异质性，并介导了疾病进展和对免疫检查点抑制剂（ICI）的反应。因此，迫切需要阐明肺癌微环境的空间定义单细胞景观，以了解疾病进展的机制，并确定对 ICI 反应的生物标志物。
在这项研究中，我们应用成像质谱细胞术来描述与疗效改善相关的激活细胞状态、细胞相互作用和邻里关系，从而描绘免疫疗法治疗非小细胞肺癌的反应中的肿瘤和免疫学景观。我们使用经抗程序性细胞死亡蛋白 1（PD-1）免疫检查点阻断治疗的癌症临床前小鼠模型对我们的发现进行了功能验证。
我们对 27 名接受 ICI 治疗的患者中的 114,524 个单细胞进行了解析，从而能够对具有不同临床结局的免疫谱系和激活状态进行空间分辨率分析。我们证明了 CXCL13 的表达与患者对 ICI 的疗效相关，并且重组 CXCL13 与增加的抗原经历 T 细胞亚群和减少的 CCR2+单核细胞一起，增强了体内抗 PD-1 反应。
我们的结果提供了一个高分辨率的分子资源，并说明了主要免疫谱系及其功能亚群在理解肿瘤免疫微环境在对 ICI 反应中的作用的重要性。
