Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells

IF 48.8 1区 医学 Q1 CELL BIOLOGY Cancer Cell Pub Date : 2024-08-29 DOI:10.1016/j.ccell.2024.08.007
Kevin Wang, Paulina Coutifaris, David Brocks, Guanning Wang, Tarek Azar, Sabrina Solis, Ajeya Nandi, Shaneaka Anderson, Nicholas Han, Sasikanth Manne, Evgeny Kiner, Chirag Sachar, Minke Lucas, Sangeeth George, Patrick K. Yan, Melanie W. Kier, Amy I. Laughlin, Shawn Kothari, Josephine Giles, Divij Mathew, Alexander C. Huang
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Abstract

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

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抗-PD-1和抗-CTLA-4疗法联合疗法产生的克隆反应波包括祖细胞耗竭的CD8+T细胞
抗PD-1和抗CTLA-4抗体联合检查点阻断疗法在黑色素瘤中显示出了良好的疗效。然而,人类的潜在机制仍不清楚。在这里,我们对36名接受抗PD-1、抗CTLA-4或联合疗法治疗的IV期黑色素瘤患者进行了成对单细胞RNA和T细胞受体(TCR)跨时间测序。我们开发了 Cyclone 算法来跟踪克隆的时间动态和潜在的细胞状态。检查点阻断诱导了一波波克隆 T 细胞反应,这些反应在不同的时间点达到峰值。与单药疗法相比,联合疗法能在6周和9周时产生更大规模的克隆反应,包括黑色素瘤特异性CD8+ T细胞和衰竭CD8+ T细胞(TEX)克隆。对TEX的集中分析表明,抗CTLA-4能诱导祖细胞TEX的强力扩增和增殖,它与抗PD-1协同作用,在联合疗法中为TEX注入新的活力。这些新一代免疫分析方法可以指导新型联合疗法的药物选择、疗程安排和剂量。
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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