Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [Singleron scTCR-seq]

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to 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 niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTreg) 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-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. scTCR-seq of sorted T cells from treatment-naïve tumor samples of ovarian cancer patients using the Singleron Biotechnologies platform Submitter states: Raw sequencing data have been deposited in the Genome Sequence Archive for Human at the National Genomics Data Center (https://ngdc.cncb.ac.cn/gsa-human) with accession number HRA007181, which will be provided for scientific research upon request complying with the law due to human patient privacy concerns.

同源重组缺陷（Homologous recombination deficiency, HRD）在癌症中高发，可使肿瘤细胞对聚腺苷二磷酸核糖聚合酶（PARP）抑制剂敏感。然而，HRD及相关疗法对肿瘤微环境（tumor microenvironment, TME）的影响仍不明确。本研究生成了来自超过100例高级别浆液性卵巢癌（high-grade serous ovarian cancer, HGSOC）样本的单细胞基因表达谱与T细胞受体谱，并配套构建了验证用多模态数据集，样本主要来自一项II期临床试验（NCT04507841）。采用PARP抑制剂尼拉帕利进行新辅助单药治疗，按照实体瘤疗效评价标准1.1版（RECIST v1.1）与妇科癌症协作组CA125（GCIG CA125）评估的客观应答率分别可达62.5%与73.6%，疗效显著。本研究鉴定出效应性调节性T细胞（effector regulatory T cells, eTreg）是HRD与新辅助治疗的关键应答细胞群，其与其他肿瘤反应性T细胞共存，尤以终末耗竭CD8+T细胞（terminally exhausted CD8+ T cells, Tex）最为突出。全肿瘤微环境范围内的干扰素信号通路与癌细胞上调主要组织相容性复合体II类（major histocompatibility complex class II, MHC-II）分子及共抑制配体的表达相关，这可能调控Treg与Tex细胞的分化命运。在HRD小鼠模型中，无论是否联合PARP抑制剂，清除eTreg均可显著抑制肿瘤生长且未观察到明显毒性，这凸显了针对eTreg的治疗策略在HGSOC及其他HRD相关肿瘤中的应用潜力。本研究使用新格元生物科技（Singleron Biotechnologies）平台，对卵巢癌患者未经治疗的肿瘤样本分选得到的T细胞开展了单细胞T细胞受体测序（single-cell T cell receptor sequencing, scTCR-seq）。项目提交方说明：原始测序数据已存入国家基因组科学数据中心的人类基因组序列归档库（Genome Sequence Archive for Human, GSA-Human），存储链接为https://ngdc.cncb.ac.cn/gsa-human，登录号为HRA007181；鉴于人类受试者隐私保护相关法规要求，相关数据将在符合法律规范的前提下，按需向科研用途开放。