Abstract：
High-grade serous tubo-ovarian cancer (HGSTOC) is an aggressive gynecological malignancy including homologous recombination deficient (HRD) and homologous recombination proficient (HRP) groups. Despite the therapeutic potential of poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-PDCD1 antibodies, acquired resistance in HRD and suboptimal response in HRP patients necessitate more precise treatment. Herein, single-cell RNA and single-cell T-cell receptor sequencing on 5 HRD and 3 HRP tumors are performed to decipher the heterogeneous tumor immune microenvironment (TIME), along with multiplex immunohistochemistry staining and animal experiments for validation. HRD tumors are enriched with immunogenic epithelial cells, FGFR1+PDGFRβ+ myCAFs, M1 macrophages, tumor reactive CD8+/CD4+ Tregs, whereas HRP tumors are enriched with HDAC1-expressing epithelial cells, indolent CAFs, M2 macrophages, and bystander CD4+/CD8+ T cells. Significantly, customized therapies are proposed. For HRD patients, targeting FGFR1+PDGFRβ+ myCAFs via tyrosine kinase inhibitors, targeting Tregs via anti-CCR8 antibodies/TNFRSF4 stimulation, and targeting CXCL13+ exhausted T cells by blocking PDCD1/CTLA-4/LAG-3/TIGIT are proposed. For HRP patients, targeting indolent CAFs, targeting M2 macrophages via CSF-1/CSF-1R inhibitors, targeting bystander T cells via tumor vaccines, and targeting epithelial cells via HDAC inhibitors. The study provides comprehensive insights into HRD and HRP TIME and tailored therapeutic approaches, addressing the challenges of PARPi-resistant HRD and refractory HRP tumors.
摘要：
高级别浆液性输卵管卵巢癌（HGSTOC）是一种侵袭性妇科恶性肿瘤，包括同源重组缺陷（HRD）和同源重组熟练（HRP）组。尽管聚（ADP-核糖）聚合酶抑制剂（PARPis）和抗PDCD1抗体具有治疗潜力，HRD的获得性耐药和HRP患者的次优反应需要更精确的治疗。在这里，对5个HRD和3个HRP肿瘤进行单细胞RNA和单细胞T细胞受体测序，以破译异质性肿瘤免疫微环境（TIME），以及多重免疫组织化学染色和动物实验进行验证。HRD肿瘤富含免疫原性上皮细胞，FGFR1+PDGFRβ+myCAFs，M1巨噬细胞，肿瘤反应性CD8+/CD4+Tregs，而HRP肿瘤富含表达HDAC1的上皮细胞，惰性CAF,M2巨噬细胞，和旁观者CD4+/CD8+T细胞。重要的是,提出了定制疗法。对于HRD患者，通过酪氨酸激酶抑制剂靶向FGFR1+PDGFRβ+myCAFs，通过抗CCR8抗体/TNFRSF4刺激靶向Tregs，并提出通过阻断PDCD1/CTLA-4/LAG-3/TIGIT靶向CXCL13+耗竭的T细胞。对于HRP患者，靶向惰性CAFs，通过CSF-1/CSF-1R抑制剂靶向M2巨噬细胞，通过肿瘤疫苗靶向旁观者T细胞，并通过HDAC抑制剂靶向上皮细胞。该研究提供了对HRD和HRP时间的全面了解以及量身定制的治疗方法，解决PARPi耐药HRD和难治性HRP肿瘤的挑战。
