Fay Magdalena, Sievers Cem, Robbins Yvette, Yang Xinping, Huynh Angel, Redman Jason M, Hodge James W, Schlom Jeffrey, Gulley James L, Allen Clint T, Craveiro Marco
Head and Neck Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
iScience. 2024 Jul 15;27(8):110520. doi: 10.1016/j.isci.2024.110520. eCollection 2024 Aug 16.
A tissue resident-like phenotype in tumor infiltrating T cells can limit systemic anti-tumor immunity. Enhanced systemic anti-tumor immunity is observed in head and neck cancer patients after neoadjuvant PD-L1 immune checkpoint blockade (ICB) and transforming growth factor β (TGF-β) neutralization. Using T cell receptor (TCR) sequencing and functional immunity assays in a syngeneic model of oral cancer, we dissect the relative contribution of these treatments to enhanced systemic immunity. The addition of TGF-β neutralization to ICB resulted in the egress of expanded and exhausted CD8 tumor infiltrating lymphocytes (TILs) into circulation and greater systemic anti-tumor immunity. This enhanced egress associated with reduced expression of (CD103) and its upstream regulator . Circulating CD8 T cells expressed higher after treatment, an observation also made in samples from patients treated with dual TGF-β neutralization and ICB. These findings provide the scientific rationale for the use of PD-L1 ICB and TGF-β neutralization in newly diagnosed patients with carcinomas prior to definitive treatment of locoregional disease.
肿瘤浸润性T细胞中类似组织驻留的表型会限制全身抗肿瘤免疫。在新辅助PD-L1免疫检查点阻断（ICB）和转化生长因子β（TGF-β）中和后，头颈部癌患者的全身抗肿瘤免疫增强。在口腔癌的同基因模型中，我们使用T细胞受体（TCR）测序和功能性免疫分析，剖析了这些治疗对增强全身免疫的相对贡献。在ICB基础上加用TGF-β中和剂，可使扩增且耗竭的CD8肿瘤浸润淋巴细胞（TILs）进入循环，并增强全身抗肿瘤免疫。这种增强的流出与（CD103）及其上游调节因子的表达降低有关。治疗后循环中的CD8 T细胞表达更高，在用双重TGF-β中和剂和ICB治疗的患者样本中也观察到了这一现象。这些发现为在局部区域疾病进行确定性治疗之前，对新诊断的癌症患者使用PD-L1 ICB和TGF-β中和剂提供了科学依据。
