比利时鲁汶大学Diether Lambrechts、Paul M. Clement课题组合作取得一项新成果。经过不懈努力，他们的研究显示CD4⁺ T细胞活化可区分，对抗程序性死亡配体1（PD-L1）+抗细胞毒性T淋巴细胞抗原-4（CTLA4）疗法和抗PD-L1单一疗法的反应。相关论文于2024年3月4日发表在《免疫》杂志上。

研究人员在头颈部鳞状细胞癌（HNSCC）患者中开展了一项机会窗口研究，以考察抗CTLA4对抗PD-L1治疗的贡献。对治疗前与治疗后活检组织进行的单细胞分析发现，T细胞扩增是早期反应的标志物。在肿瘤中，抗PD-L1主要引起CD8⁺ T细胞的扩增，而联合疗法则会导致CD4⁺和CD8⁺ T细胞同时扩增。这些CD4⁺ T细胞表现出活化的辅助性T细胞1（Th1）表型。CD4⁺和CD8⁺ T细胞与表达T细胞归巢因子的树突状细胞或产生抗体的浆细胞共定位，并被其包围。

T细胞受体追踪表明，抗CTLA4（而非抗PD-L1）会触发CD4⁺原始/中央记忆T细胞，从肿瘤引流淋巴结（tdLN）经血液转移到肿瘤，T细胞在肿瘤中获得Th1表型。因此，CD4⁺ T细胞活化和从tdLNs招募是HNSCC对抗PD-L1加抗CTLA4早期反应的标志。

研究人员表示，癌症患者通常会接受针对PD-L1和CTLA4的联合抗体治疗。

附：原文原文

Title: CD4+ T cell activation distinguishes response to anti-PD-L1+anti-CTLA4 therapy from anti-PD-L1 monotherapy

Author: Amelie Franken, Michel Bila, Aurelie Mechels, Sam Kint, Jeroen Van Dessel, Valentina Pomella, Sebastiaan Vanuytven, Gino Philips, Orian Bricard, Jieyi Xiong, Bram Boeckx, Sigrid Hatse, Thomas Van Brussel, Rogier Schepers, Cedric Van Aerde, Sarah Geurs, Vincent Vandecaveye, Esther Hauben, Vincent Vander Poorten, Sara Verbandt, Katy Vandereyken, Junbin Qian, Sabine Tejpar, Thierry Voet, Paul M. Clement, Diether Lambrechts

Issue&Volume: 2024-03-04

Abstract: Cancer patients often receive a combination of antibodies targeting programmed death-ligand1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunitystudy in head and neck squamous cell carcinoma (HNSCC) to examine the contributionof anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatmentbiopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1triggered the expansion of mostly CD8+ T cells, whereas combination therapy expanded both CD4+ and CD8+ T cells. Such CD4+ T cells exhibited an activated T helper 1 (Th1) phenotype. CD4+ and CD8+ T cells co-localized with and were surrounded by dendritic cells expressing T cellhoming factors or antibody-producing plasma cells. T cell receptor tracing suggeststhat anti-CTLA4, but not anti-PD-L1, triggers the trafficking of CD4+ naive/central-memory T cells from tumor-draining lymph nodes (tdLNs), via blood,to the tumor wherein T cells acquire a Th1 phenotype. Thus, CD4+ T cell activation and recruitment from tdLNs are hallmarks of early response to anti-PD-L1plus anti-CTLA4 in HNSCC.

DOI: 10.1016/j.immuni.2024.02.007

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00083-9