不同的CD8⁺ T细胞动力学与新辅助癌症免疫治疗的反应相关，这一成果由UPMC希尔曼癌症中心Robert L. Ferris研究团队经过不懈努力而取得。相关论文于2025年3月13日发表在《癌细胞》杂志上。

小组利用一项临床试验（NCT04080804）比较了新辅助抗PD-1、抗PD-1+CTLA-4和抗PD-1+LAG-3治疗在头颈部鳞状细胞癌患者中的应用。联合治疗比单药治疗有更高的病理反应率，主要病理反应与更好的生存率相关。为了解决成功的免疫检查点抑制剂（ICI）方案是否通过相似或不同的途径起作用，该课题组以克隆方式对CD8⁺肿瘤浸润淋巴细胞（TILs）的转录和蛋白质组学动力学进行了随机和纵向表征。Anti-PD-1+LAG-3将CD8⁺ TIL与i型干扰素反应和衰竭基因程序重编程为效应记忆和常驻记忆（TEM/TRM）。相比之下，抗PD-1+CTLA-4激活并扩展已有的TEM/TRM CD8⁺ TIL，但不会将耗尽的表型恢复为T效应细胞。Anti-PD-1+LAG-3，而不是Anti-PD-1+ CTLA-4，诱导TCR在不同转录状态之间广泛共享，并增加应答患者的TCR多样性。他们的数据表明肿瘤反应性CD8⁺ T细胞的双重方案特异性转录和克隆动力学。

附：英文原文

Title: Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies

Author: Housaiyin Li, Dan P. Zandberg, Aditi Kulkarni, Simion I. Chiosea, Patricia M. Santos, Brian R. Isett, Marion Joy, Gabriel L. Sica, Kevin J. Contrera, Curtis M. Tatsuoka, Matthias Brand, Umamaheswar Duvvuri, Seungwon Kim, Mark Kubik, Shaum Sridharan, Fei Tu, Jie Chen, Tullia C. Bruno, Dario A.A. Vignali, Anthony R. Cillo, Riyue Bao, Jing Hong Wang, Lazar Vujanovic, Robert L. Ferris

Issue&Volume: 2025-03-13

Abstract: We leverage a clinical trial (NCT04080804) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8+ tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8+ TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (TEM/TRM). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing TEM/TRM CD8+ TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8+ T cells.

DOI: 10.1016/j.ccell.2025.02.026

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00078-9