Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors

• DOI: 10.1016/j.cell.2024.06.013
• Publication Date: 2024-07-05T14:54:47Z
• Authors: 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
• Keywords: Treg cell

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 microenvironment (TME) remains elusive. Our study generates single-cell gene expression T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy PARP inhibitor (PARPi) niraparib achieves impressive 62.5% 73.6% response rates per RECIST v.1.1 GCIG CA125, respectively. We identify effector regulatory (eTregs) as key responders neoadjuvant therapies, co-occurring other tumor-reactive cells, particularly terminally exhausted CD8+ (Tex). TME-wide interferon signaling correlates upregulating MHC class co-inhibitory ligands, potentially driving Treg Tex fates. Depleting eTregs mouse models, or without inhibition, significantly suppresses growth observable toxicities, underscoring potential eTreg-focused therapeutics for HGSOC HRD-related tumors.