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2022, Nature Cancer. DOI: 10.1038/s43018-022-00352-7 PMID: 35393580 PMCID: PMC9050907
Concurrent delivery of immune checkpoint blockade modulates T cell dynamics to enhance neoantigen vaccine-generated antitumor immunity
Abstract:
Neoantigen vaccines aiming to induce tumor-specific T cell responses have achieved promising antitumor effects in early clinical trials. However, the underlying mechanism regarding response or resistance to this treatment is unclear. Here we observe that neoantigen vaccine-generated T cells can synergize with the immune checkpoint blockade for effective tumor control. Specifically, we performed single-cell sequencing on over 100,000 T cells and uncovered that combined therapy induces an antigen-specific CD8 T cell population with active chemokine signaling (Cxcr3+/Ccl5+), lower co-inhibitory receptor expression (Lag3−/Havcr2−) and higher cytotoxicity (Fasl+/Gzma+). Furthermore, generation of neoantigen-specific T cells in the draining lymph node is required for combination treatment. Signature genes of this unique population are associated with T cell clonal frequency and better survival in humans. Our study profiles the dynamics of tumor-infiltrating T cells during neoantigen vaccine and immune checkpoint blockade treatments and high-dimensionally identifies neoantigen-reactive T cell signatures for future development of therapeutic strategies.
2022-04-28 10:15:00
#paper doi.org/10.1038/s43018-022-00352-7 Concurrent delivery of immune checkpoint blockade modulates T cell dynamics to enhance neoantigen vaccine-generated antitumor immunity Nat Cancer (2022). 一篇介绍新生抗原疫苗(ADP 依赖性葡糖激酶突变的 9 聚体 (ADPGK))和免疫检查点抑制剂联合治疗的文章。作者通过对 MC38 模型进行新抗原疫苗接种、抗 PD-L1 治疗和联合治疗期间 DLN 和肿瘤组织中的 T 细胞进行了单细胞 RNA 测序 (scRNA-seq)。通过聚类表征,对簇间 TCR 的相似性 、克隆共享迁移分数、T 细胞进化轨迹、迁移抑制等分析跟踪 TME 的时空状态转换,1.验证了联合治疗通过对 TME 诱导 防止 Teff 细胞向终末耗竭 T 细胞的转变,以及 来自 DLN 的新浸润新抗原特异 T 细胞迁移对促进持久的免疫反应至关重要2.另一种 MC38 表位特异的 T 细胞百分比在联合治疗后也显着增加,Teff 细胞可能在原始肿瘤抗原初始引发后经历表位扩散。3.使用 IFN-γ 途径中的三个基因:Ifngr1、Zfp36l2 和 Gimap4 和两个趋化因子相关基因(Ccl5 和CXCR3) 刻画 MC38 癌症模型 ADPGK 新抗原特异性 T 细胞 (CAST) 评分,ICB 治疗增加了四分之三患者的 CAST 评分, ICB 在扩大 TME 中抗原特异性 T 细胞中的作用。作者分析使用了 10d 和 20d 的时间点的测序数据,从本文来看其分析和模型还是受到 小鼠模型 、疫苗特异性 、 临床数据 、时间梯度 的局限性。
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