Molecular Microbiology and Immunology Department, Saint Louis University School of Medicine, 1100 South Grand Blvd, St. Louis, MO, 63104, USA.
Genomics Core Facility, Saint Louis University School of Medicine, St. Louis, MO, USA.
Cancer Immunol Immunother. 2023 Feb;72(2):397-408. doi: 10.1007/s00262-022-03263-9. Epub 2022 Jul 30.
Checkpoint blockade immunotherapy has become a first-line treatment option for cancer patients, with success in increasingly diverse cancer types. Still, many patients do not experience durable responses and the reasons for clinical success versus failure remain largely undefined. Investigation of immune responses within the tumor microenvironment can be highly informative but access to tumor tissue is not always available, highlighting the need to identify biomarkers in the blood that correlate with clinical success. Here, we used single-cell RNA sequencing coupled with T cell receptor sequencing to define CD8 T cell responses in peripheral blood of two patients with melanoma before and after immunotherapy with either anti-PD-1 (nivolumab) alone or the combination of anti-PD-1 and CTLA-4 (ipilimumab). Both treatment regimens increased transcripts associated with cytolytic effector function and decreased transcripts associated with naive T cells. These responses were further evaluated at the protein level and extended to a total of 53 patients with various cancer types. Unexpectedly, the induction of CD8 T cell responses associated with cytolytic function was variable and did not predict therapeutic success in this larger patient cohort. Rather, a decrease in the frequency of T cells with a naive-like phenotype was consistently observed after immunotherapy and correlated with prolonged patient survival. In contrast, a more detailed clonotypic analysis of emerging and expanding CD8 T cells in the blood revealed that a majority of individual T cell clones responding to immunotherapy acquired a transcriptional profile consistent with cytolytic effector function. These results suggest that responses to checkpoint blockade immunotherapy are evident and traceable in patients' blood, with outcomes predicted by the simultaneous loss of naive-like CD8 T cells and the expansion of mostly rare and diverse cytotoxic CD8 T cell clones.
检查点阻断免疫疗法已成为癌症患者的一线治疗选择，在越来越多的癌症类型中取得了成功。然而，许多患者并未获得持久的反应，临床成功与失败的原因仍在很大程度上未得到明确。对肿瘤微环境中的免疫反应进行研究可以提供很多信息，但并非总是能够获得肿瘤组织，这凸显了需要在血液中识别与临床成功相关的生物标志物的需求。在这里，我们使用单细胞 RNA 测序和 T 细胞受体测序，在两名接受抗 PD-1（nivolumab）单药或抗 PD-1 和 CTLA-4（ipilimumab）联合治疗的黑色素瘤患者的治疗前后，在其外周血中定义了 CD8 T 细胞反应。两种治疗方案均增加了与细胞毒性效应功能相关的转录本，并减少了与幼稚 T 细胞相关的转录本。这些反应在蛋白质水平上进一步进行了评估，并扩展到总共 53 名患有各种癌症类型的患者。出乎意料的是，与细胞毒性功能相关的 CD8 T 细胞反应的诱导是可变的，并且在更大的患者队列中并未预测治疗成功。相反，在免疫治疗后，始终观察到具有类似幼稚表型的 T 细胞频率降低，与患者的生存延长相关。相比之下，对血液中新兴和扩增的 CD8 T 细胞进行更详细的克隆型分析表明，大多数对免疫治疗有反应的个体 T 细胞克隆获得了与细胞毒性效应功能一致的转录谱。这些结果表明，检查点阻断免疫疗法的反应在患者的血液中是明显的且可追踪的，其结果可通过同时丧失类似幼稚的 CD8 T 细胞和扩增大多数稀有和多样化的细胞毒性 CD8 T 细胞克隆来预测。
