华中科技大学高庆蕾，方勇，马丁和美国德克萨斯大学MD安德森癌症中心梁晗合作取得进展。他们研究提出卵巢癌新辅助PARPi或化疗可以为靶向效应Treg细胞，治疗同源重组缺陷肿瘤提供策略依据。相关研究成果2024年7月5日在线发表于《细胞》杂志上。
据介绍，同源重组缺陷（HRD）在癌症中普遍存在，使肿瘤细胞对多聚ADP-核糖聚合酶（PARP）抑制敏感。然而，HRD及相关疗法对肿瘤微环境（TME）的影响尚不清楚。
研究人员分析了单细胞基因表达和T细胞受体谱，以及来自超过100个高级别浆液性卵巢癌（HGSOC）样本的验证性多模式数据集，这些样本主要来自II期临床试验（NCT04507841）。PARP抑制剂（PARPi）niraparib的新辅助单药治疗根据RECIST v.1.1和GCIG CA125，分别实现了62.5%和73.6%的显著效率。
效应调节性T细胞（eTreg）是对HRD和新辅助疗法的关键响应者，伴随着其他肿瘤反应性T细胞，特别是终末衰竭的CD8+ T细胞（Tex）。整个TME中的干扰素信号与癌细胞上调MHC II类分子和共抑制配体相关，可能驱动Treg和Tex的命运。
总之，在HRD小鼠模型中耗竭eTreg，无论是否伴随PARP抑制，都显著抑制了肿瘤生长且无明显毒性，这突显了以eTreg为靶点对治疗HGSOC及其他HRD相关肿瘤的潜力。
附：英文原文
Title: Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors
Author: Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Ding Ma, Yong Fang, Han Liang, Qinglei Gao
Issue&Volume: 2024-07-05
Abstract: Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
DOI: 10.1016/j.cell.2024.06.013
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00653-6