Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
J Immunother Cancer. 2020 Mar;8(1). doi: 10.1136/jitc-2019-000251.
Malignant pleural mesothelioma (MPM) is a highly lethal malignancy in need for new treatment options. Although immunotherapies have been shown to boost a tumor-specific immune response, not all patients respond and prognostic biomarkers are scarce. In this study, we determined the peripheral blood T cell receptor β (TCRβ) chain repertoire of nine MPM patients before and 5 weeks after the start of dendritic cell (DC)-based immunotherapy.
We separately profiled PD1 and PD1CD4 and CD8 T cells, as well as Tregs and analyzed 70 000 TCRβ sequences per patient.
Strikingly, limited TCRβ repertoire diversity and high average clone sizes in total CD3 T cells before the start of immunotherapy were associated with a better clinical response. To explore the differences in TCRβ repertoire prior-DC-therapy and post-DC-therapy, for each patient the TCRβ clones present in the total CD3 T cell fractions were classified into five categories, based on therapy-associated frequency changes: expanding, decreasing, stable, newly appearing and disappearing clones. Subsequently, the presence of these five groups of clones was analyzed in the individual sorted T cell fractions. DC-therapy primarily induced TCRβ repertoire changes in the PD1CD4 and PD1CD8 T cell fractions. In particular, in the PD1CD8 T cell subpopulation we found high frequencies of expanding, decreasing and newly appearing clones. Conversion from a PD1 to a PD1 phenotype was significantly more frequent in CD8 T cells than in CD4 T cells. Hereby, the number of expanding PD1CD8 T cell clones-and not expanding PD1CD4 T cell clones following immunotherapy positively correlated with overall survival, progression-free survival and reduction of tumor volume.
We conclude that the clinical response to DC-mediated immunotherapy is dependent on both the pre-existing TCRβ repertoire of total CD3 T cells and on therapy-induced changes, in particular expanding PD1CD8 T cell clones. Therefore, TCRβ repertoire profiling in sorted T cell subsets could serve as predictive biomarker for the selection of MPM patients that benefit from immunotherapy.
NCT02395679.
恶性胸膜间皮瘤（MPM）是一种高度致命的恶性肿瘤，需要新的治疗选择。尽管免疫疗法已被证明可以增强肿瘤特异性免疫反应，但并非所有患者都有反应，且预后生物标志物稀缺。在这项研究中，我们在开始树突状细胞（DC）免疫治疗之前和之后 5 周，测定了 9 名 MPM 患者的外周血 T 细胞受体β（TCRβ）链谱。
我们分别对 PD1 和 PD1CD4 和 CD8 T 细胞进行了分析，并对每个患者的 70000 个 TCRβ 序列进行了分析。
令人惊讶的是，在开始免疫治疗之前，总 CD3 T 细胞中有限的 TCRβ 谱多样性和高平均克隆大小与更好的临床反应相关。为了探索治疗前和治疗后 TCRβ 谱的差异，我们根据治疗相关的频率变化，将每个患者的总 CD3 T 细胞中存在的 TCRβ 克隆分为五类：扩增、减少、稳定、新出现和消失的克隆。随后，在个体分选的 T 细胞群中分析了这五类克隆的存在。DC 治疗主要诱导 PD1CD4 和 PD1CD8 T 细胞群中 TCRβ 谱的变化。特别是在 PD1CD8 T 细胞亚群中，我们发现了扩增、减少和新出现克隆的高频率。CD8 T 细胞中从 PD1 到 PD1 的转换明显比 CD4 T 细胞更频繁。因此，免疫治疗后，扩增的 PD1CD8 T 细胞克隆的数量-而不是扩增的 PD1CD4 T 细胞克隆的数量-与总生存期、无进展生存期和肿瘤体积缩小呈正相关。
我们得出结论，DC 介导的免疫治疗的临床反应既依赖于总 CD3 T 细胞的预先存在的 TCRβ 谱，也依赖于治疗诱导的变化，特别是扩增的 PD1CD8 T 细胞克隆。因此，分选 T 细胞亚群中的 TCRβ 谱分析可以作为预测标志物，选择从免疫治疗中获益的 MPM 患者。
NCT02395679。
