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. 2024 Jul 5:S0092-8674(24)00653-6.
doi: 10.1016/j.cell.2024.06.013. Online ahead of print.

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

Yikai Luo  1 , Yu Xia  2 , Dan Liu  2 , Xiong Li  3 , Huayi Li  2 , Jiahao Liu  2 , Dongchen Zhou  2 , Yu Dong  4 , Xin Li  2 , Yiyu Qian  2 , Cheng Xu  2 , Kangjia Tao  2 , Guannan Li  2 , Wen Pan  2 , Qing Zhong  2 , Xingzhe Liu  2 , Sen Xu  2 , Zhi Wang  3 , Ronghua Liu  2 , Wei Zhang  2 , Wanying Shan  2 , Tian Fang  2 , Siyuan Wang  2 , Zikun Peng  2 , Ping Jin  2 , Ning Jin  2 , Shennan Shi  2 , Yuxin Chen  2 , Mengjie Wang  2 , Xiaofei Jiao  2 , Mengshi Luo  2 , Wenjian Gong  2 , Ya Wang  2 , Yue Yao  4 , Yi Zhao  4 , Xinlin Huang  4 , Xuwo Ji  4 , Zhaoren He  5 , Guangnian Zhao  2 , Rong Liu  2 , Mingfu Wu  2 , Gang Chen  2 , Li Hong  6 ; COCPO Consortium; Ding Ma  7 , Yong Fang  8 , Han Liang  9 , Qinglei Gao  10
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Free article

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

Yikai Luo et al. Cell. .
Free article

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.

Keywords: CCR8; HGSOC; HRD; PARP inhibitor; chemotherapy; effector Treg; neoadjuvant therapy; single-cell transcriptomics; tumor microenvironment; tumor-reactive T cell.

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Conflict of interest statement

Declaration of interests Y.Y., Y.D., Y.Z., X.H., and X. Ji are full-time employees and H. Liang is a shareholder and scientific advisor of Precision Scientific Ltd. Z.H. is a full-time employee of BioMap Intelligence Technology.

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