Background: Ovarian cancer is an immunologically cold tumor that is treated with surgery and a chemotherapy regimen of platinum agents with taxanes. Paradoxically, elevated levels of several immune markers are effective at predicting prognosis for patients with ovarian cancer, though it is not clear how chemotherapy might influence this. Chemotherapy elicits immunogenic cell death, yet tumor-controlling doses of chemotherapy are also immunotoxic. Objectives: To evaluate interactions of chemotherapy with the immune system, we studied the impact of chemotherapy in an aggressive mouse model of ovarian cancer developed within our lab. Methods: Using a single-cell transcriptomics sequencing approach, supported by flow cytometry, we evaluated the influence of a first-line therapy, cisplatin and docetaxel, and a second-line therapy, pegylated liposomal doxorubicin (PLD), on control of tumor growth and on tumor-associated immune populations of cells. Results: Both chemotherapy approaches were effective at controlling tumor growth and selectively depleted tumor cells from distinct transcriptional clusters. Both chemotherapies also resulted in relative increases in immune populations compared to untreated tumor-bearing mice, but immune populations from PLD-treated mice were more abundant and expressed a greater fraction of maturity-associated transcripts and increased proportions of tumor resident macrophage populations. PLD treatment selectively upregulated MHC class II on tumor cells, and this could be replicated in vitro across ovarian cancer cell lines and in patient tumor cells ex vivo. Conclusions: Altogether, the results support the notion that PLD has a greater capacity for immunopotentiation, which may be important to consider if immunotherapy approaches are adapted for ovarian tumors in the future.
背景：卵巢癌是一种免疫学上的冷肿瘤，通常采用手术联合铂类与紫杉烷类化疗方案进行治疗。矛盾的是，尽管化疗可能如何影响尚不明确，但多项免疫标志物水平的升高能有效预测卵巢癌患者的预后。化疗可引发免疫原性细胞死亡，但控制肿瘤的化疗剂量同时也具有免疫毒性。目的：为评估化疗与免疫系统的相互作用，我们在实验室建立的侵袭性卵巢癌小鼠模型中研究了化疗的影响。方法：采用单细胞转录组测序技术，并辅以流式细胞术验证，我们评估了一线疗法（顺铂和多西他赛）和二线疗法（聚乙二醇化脂质体阿霉素，PLD）对肿瘤生长控制及肿瘤相关免疫细胞群的影响。结果：两种化疗方案均能有效控制肿瘤生长，并选择性清除不同转录簇中的肿瘤细胞。与未治疗的荷瘤小鼠相比，两种化疗均导致免疫细胞群相对增加，但PLD治疗组小鼠的免疫细胞群更为丰富，表达更高比例的成熟相关转录本，且肿瘤驻留巨噬细胞群比例增加。PLD治疗能选择性上调肿瘤细胞上的MHC II类分子，这一现象在体外多个卵巢癌细胞系及离体患者肿瘤细胞中均可复现。结论：总体而言，这些结果支持PLD具有更强的免疫增强能力，若未来将免疫疗法应用于卵巢肿瘤治疗，这一特性可能具有重要意义。
肿瘤(癌症)患者之家