免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
克隆多样性 CXCR5+ B 细胞向 CD4 和 CD8 T 细胞呈递抗原与免疫检查点抑制剂的持久反应相关
英文原题：Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.
查看英文原题
Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.
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研究概要
对 ICI 的应答，而非对 MAPKi 的应答，取决于 CXCR5+ B 细胞被招募到肿瘤微环境中，以及它们向滤泡辅助性和细胞毒性、肿瘤反应性 T 细胞有效呈递肿瘤抗原。我们的研究强调了 CXCL13 和基于 B 细胞的策略在提高接受 ICI 治疗的黑色素瘤患者持久缓解率方面的潜力。
研究思路结论见上方概要
背景
在对ICI（免疫检查点抑制剂）或MAPK通路抑制剂（MAPKi）疗法有反应的黑色素瘤患者肿瘤中，可见T细胞浸润增加和干扰素γ（IFNγ）通路激活。然而，ICI后持久肿瘤控制率几乎是MAPKi的两倍，提示对ICI疗法有反应的患者中可能存在额外机制，这些机制对抗肿瘤免疫有益。
方法
我们利用转录分析和接受ICI或MAPKi治疗的患者的临床结局，来阐明驱动肿瘤反应的免疫机制。
结果
我们发现对ICI的应答与CXCL13驱动的CXCR5+ B细胞募集相关，且其克隆多样性显著高于MAPKi。我们的体外数据表明，抗PD1治疗可增加人外周血单个核细胞中CXCL13的产生，而MAPKi治疗则不能。更高的B细胞浸润和B细胞受体（BCR）多样性使B细胞能够呈递多种肿瘤抗原，从而在ICI治疗后激活滤泡辅助性CD4 T细胞（Tfh）和肿瘤反应性CD8 T细胞。ICI治疗后较高的BCR多样性和IFNγ通路评分与患者生存期显著延长相关，优于仅具有其中一项或均无的患者。
展开英文摘要原文
METHODS
We used transcriptional analysis and clinical outcomes from patients treated with ICI or MAPKi therapies to delineate immune mechanisms driving tumor response.
RESULTS
We discovered response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with significantly higher clonal diversity than MAPKi. Our in vitro data indicate that CXCL13 production was increased in human peripheral blood mononuclear cells by anti-PD1, but not MAPKi, treatment. Higher B cell infiltration and B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in activation of follicular helper CD4 T cells (Tfh) and tumor reactive CD8 T cells after ICI therapy. Higher BCR diversity and IFNγ pathway score post-ICI are associated with significantly longer patient survival compared to those with either one or none.
CONCLUSIONS
Response to ICI, but not to MAPKi, depends on the recruitment of CXCR5+ B cells into the tumor microenvironment and their productive tumor antigen presentation to follicular helper and cytotoxic, tumor reactive T cells. Our study highlights the potential of CXCL13 and B cell based strategies to enhance the rate of durable response in melanoma patients treated with ICI.
论文信息
- 作者
- Ding L、Sun L、Bu MT、Zhang Y、Scott LN、Prins RM、Su MA、Lechner MG
- 单位
- Department of Medicine, Division of Dermatology, University of California, Los Angeles, Los Angeles, CA, United States.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Frontiers in immunology2023
- 原文标识
- PubMed 37435085 · DOI 10.3389/fimmu.2023.1176994
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