阻断 LAG-3 和 PD-1 会导致 CD8 T 细胞中细胞毒性和耗竭基因模块的共表达，从而促进抗肿瘤免疫。
Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity.
发表日期：2024 Aug 08
作者：
Anthony R Cillo, Carly Cardello, Feng Shan, Lilit Karapetyan, Sheryl Kunning, Cindy Sander, Elizabeth Rush, Arivarasan Karunamurthy, Ryan C Massa, Anjali Rohatgi, Creg J Workman, John M Kirkwood, Tullia C Bruno, Dario A A Vignali
来源：
CELL
摘要：
Relatlimab（rela；抗 LAG-3）联合 nivolumab（nivo；抗 PD-1）对于治疗晚期黑色素瘤是安全有效的。我们设计了一项试验 (NCT03743766)，晚期黑色素瘤患者接受 rela、nivo 或 rela nivo 治疗，以探究 rela nivo 的免疫机制。对这项正在进行的试验的生物样本的分析表明，rela nivo 可增强 CD8 T 细胞受体信号传导能力并改变 CD8 T 细胞分化，从而导致细胞毒性增强，尽管保留了衰竭特征。细胞毒性和耗竭特征的共表达由 PRDM1、BATF、ETV7 和 TOX 驱动。在 rela nivo 后出现的克隆扩增的 CD8 T 细胞中，效应器功能上调。肿瘤内相关 CD8 T 细胞特征与良好的预后相关。这种肿瘤内的 rela nivo 特征在外周血中得到了验证，即 CD38 TIM3 CD8 T 细胞频率升高。总体而言，我们证明，尽管保留了衰竭特征，细胞毒性仍可增强，这将为未来的治疗策略提供信息。版权所有 © 2024 Elsevier Inc. 保留所有权利。
Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.Copyright © 2024 Elsevier Inc. All rights reserved.