Liu Xiu-Feng, Song Bin, Sun Chang-Bin, Zhu Qian, Yue Jian-Hui, Liang Yu-Jing, He Jia, Zeng Xi-Liang, Qin Ye-Chi, Chen Qiu-Yan, Mai Hai-Qiang, Zhang Xi, Li Jiang
Department of Biotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
BGI, Shenzhen 518083, P.R. China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
Cell Rep Med. 2025 May 20;6(5):102096. doi: 10.1016/j.xcrm.2025.102096. Epub 2025 May 1.
Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has demonstrated clinical success in solid tumors. We analyze 47 TIL infusion products and 62 pretreatment tumor microenvironments (TMEs) from a randomized phase 2 clinical study of concurrent chemoradiotherapy plus TIL-ACT (NCT02421640). Using single-cell and bulk RNA sequencing along with flow cytometry, we identify 14 CD3 T cell clusters within 26 TIL infusion products: 11 CD3CD8 TILs, 2 CD3CD4 TILs, and 1 CD3CD8CD4 double-negative (DN) TIL. (DN) TILs, significantly associated with poor TIL-ACT outcomes, exhibit an activated regulatory T cell-like phenotype and include two CD56 and four CD56 subsets. Among them, CD56KZF2 (DN) TILs are predominantly suppressive. (DN) TILs inhibit CD8 TIL expansion via Fas-FasL, transforming growth factor β (TGF-β), and interleukin (IL)-10 signaling. Distinct CD8 T subsets differentially impact on TIL-ACT outcomes, while 9 baseline TME gene signatures and 14 intracellular T cell genes hold prognostic value. Our findings identify predictive TIL subsets and biomarkers for TIL-ACT outcomes.
采用肿瘤浸润淋巴细胞（TILs）的过继性细胞疗法（ACT）已在实体瘤治疗中取得临床成功。我们分析了一项同步放化疗加TIL-ACT的随机2期临床研究（NCT02421640）中的47个TIL输注产品和62个预处理肿瘤微环境（TME）。通过单细胞和批量RNA测序以及流式细胞术，我们在26个TIL输注产品中鉴定出14个CD3 T细胞簇：11个CD3CD8 TIL、2个CD3CD4 TIL和1个CD3CD8CD4双阴性（DN）TIL。（DN）TIL与TIL-ACT疗效不佳显著相关，表现出活化调节性T细胞样表型，包括两个CD56和四个CD56亚群。其中，CD56KZF2（DN）TIL主要具有抑制作用。（DN）TIL通过Fas-FasL、转化生长因子β（TGF-β）和白细胞介素（IL）-10信号传导抑制CD8 TIL扩增。不同的CD8 T亚群对TIL-ACT疗效有不同影响，而9个基线TME基因特征和14个细胞内T细胞基因具有预后价值。我们的研究结果确定了TIL-ACT疗效的预测性TIL亚群和生物标志物。
