近日，美国宾夕法尼亚大学Alexander C. Huang等研究人员合作发现，抗PD-1和抗CTLA-4联合治疗可产生克隆性反应波，其中包括衰竭前体CD8⁺ T细胞。该项研究成果于2024年8月29日在线发表在《癌细胞》杂志上。

研究人员表示，抗PD-1和抗CTLA-4抗体的联合免疫检查点阻断治疗已在黑色素瘤中显示出令人鼓舞的疗效。然而，其在人体中的潜在机制尚不清楚。

为了解决这一问题，研究人员对36名接受抗PD-1、抗CTLA-4或联合治疗的IV期黑色素瘤患者进行了配对的单细胞RNA测序和T细胞受体（TCR）测序。研究人员开发了名为Cyclone的算法，用于追踪时间上的克隆动态和潜在的细胞状态。结果显示，免疫检查点阻断诱导了克隆性T细胞反应波，在不同时间点达到高峰。

与单药治疗相比，联合治疗在治疗后的第6周和第9周产生了更大幅度的克隆性反应，包括黑色素瘤特异性CD8⁺ T细胞和衰竭CD8⁺ T细胞（T_EX）克隆。进一步分析T_EX表明，抗CTLA-4可显著扩展和增殖衰竭前体T_EX，并与抗PD-1协同，在联合治疗期间使T_EX重新活化。这些新一代的免疫分析方法可以指导药物选择、治疗时间表及剂量的制定，从而为新的联合治疗策略提供依据。

附：英文原文

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

Author: 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, Reem Ghinnagow, Cecile Alanio, Ahron Flowers, Wei Xu, Daniel J. Tenney, Xiaowei Xu, Ravi K. Amaravadi, Giorgos C. Karakousis, Lynn M. Schuchter, Marcus Buggert, Derek Oldridge, Andy J. Minn, Christian Blank, Jeffrey S. Weber, Tara C. Mitchell, Michael D. Farwell, Ramin S. Herati, Alexander C. Huang

Issue&Volume: 2024-08-29

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.

DOI: 10.1016/j.ccell.2024.08.007

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00306-4