Shen Yuanming, Ren Yan, Chen Kelie, Cen Yixuan, Zhang Bo, Lu Weiguo, Xu Junfen
Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Oncogenesis. 2022 Jul 30;11(1):43. doi: 10.1038/s41389-022-00419-1.
High-grade serous ovarian, fallopian tube or peritoneal carcinoma is an aggressive subtype of ovarian cancer that frequently develops resistance to chemotherapy. It remains contested whether the resistance is caused by the acquisition of novel molecular aberrations or alternatively through the selection of rare pre-existing tumor clones. To address this question, we applied single-cell RNA sequencing to depict the tumor landscape of 6 samples from a single case of advanced high-grade serous fallopian tube carcinoma during neoadjuvant chemotherapy (NACT). We analyzed a total of 32,079 single cells, with 17,249 cells derived from the pre-NACT multisite tumor tissue samples and 14,830 cells derived from the post-NACT multisite tumor tissue samples. We identified the diverse properties of the tumor, immune and stromal cell types between the pre-NACT and post-NACT tumors. The malignant epithelial cells displayed a high degree of intratumor heterogeneity in response to NACT. We showed that the primary resistant clone (clone 63) epithelial genotype was already present in the pre-NACT tumors, and was adaptively enriched after NACT. This clone 63 was correlated with a poor clinical prognosis. Furthermore, single-cell analysis of CD4 T cells demonstrated that IL2RAhi-CCL22+-Tregs were selectively enriched in post-NACT tumors. Interestingly, this Treg subtype could recruit and enrich themselves through secreting the CCL22-CCR1 combination in pre-NACT and post-NACT tumors, and further express CD274 to suppress other CD4 and CD8 T cells through a CD274-PDCD1 axis in the post-NACT tumors, and this predicted an immunosuppressive state after NACT. Overall, our results provide important evidence for the adaptive resistance theory of HGSC, and for the potential development of therapeutic strategies to treat HGSC and improve the survival of patients with HGSC.
高级别浆液性卵巢癌、输卵管癌或腹膜癌是卵巢癌的一种侵袭性亚型，常对化疗产生耐药性。耐药性是由获得新的分子异常引起，还是通过选择罕见的预先存在的肿瘤克隆导致，目前仍存在争议。为了解决这个问题，我们应用单细胞RNA测序来描绘1例晚期高级别浆液性输卵管癌患者在新辅助化疗（NACT）期间6个样本的肿瘤图谱。我们总共分析了32079个单细胞，其中17249个细胞来自NACT前的多部位肿瘤组织样本，14830个细胞来自NACT后的多部位肿瘤组织样本。我们确定了NACT前和NACT后肿瘤之间肿瘤、免疫和基质细胞类型的不同特性。恶性上皮细胞对NACT的反应显示出高度的肿瘤内异质性。我们发现主要的耐药克隆（克隆63）上皮基因型在NACT前的肿瘤中已经存在，并在NACT后适应性富集。这个克隆63与不良的临床预后相关。此外，对CD4 T细胞的单细胞分析表明，IL2RAhi-CCL22+-Tregs在NACT后的肿瘤中选择性富集。有趣的是，这种Treg亚型可以通过在NACT前和NACT后的肿瘤中分泌CCL22-CCR1组合来招募和富集自身，并在NACT后的肿瘤中通过CD274-PDCD1轴进一步表达CD274来抑制其他CD4和CD8 T细胞，这预示着NACT后的免疫抑制状态。总体而言，我们的结果为HGSC的适应性耐药理论以及治疗HGSC和改善HGSC患者生存率的治疗策略的潜在发展提供了重要证据。
