Abstract

Cancer immunotherapy has seen significant success in the last decade for cancer management by enhancing endogenous cancer immunity. However, immunotherapies developed thus far have seen limited success in the majority of high-grade serous carcinoma (HGSC) ovarian cancer patients. This is largely due to the highly immunosuppressive tumour microenvironment of HGSC and late-stage identification. Thus, novel treatment interventions are needed to overcome this immunosuppression and complement existing immunotherapies. Here, we have identified through analysis of > 600 human HGSC tumours a critical role for Let-7i in modulating the tumoural immune network. Tumoural expression of Let-7i had high positive correlation with anti-cancer immune signatures in HGSC patients. Confirming this role, enforced Let-7i expression in murine HGSC tumours resulted in a significant decrease in tumour burden with a significant increase in tumour T cell numbers in tumours. In concert with the improved tumoural immunity, Let-7i treatment also significantly increased CD86 expression in antigen presenting cells (APCs) in the draining lymph nodes, indicating enhanced APC activity. Collectively, our findings highlight an important role of Let-7i in anti-tumour immunity and its potential use for inducing an anti-tumour effect in HGSC.

中文翻译：

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Let-7i增强抗肿瘤免疫力并抑制卵巢肿瘤生长

摘要

过去十年，癌症免疫疗法通过增强内源性癌症免疫力，在癌症治疗方面取得了巨大成功。然而，迄今为止开发的免疫疗法在大多数高级别浆液性癌（HGSC）卵巢癌患者中取得的成功有限。这很大程度上是由于 HGSC 的高度免疫抑制肿瘤微环境和后期鉴定。因此，需要新的治疗干预措施来克服这种免疫抑制并补充现有的免疫疗法。在这里，我们通过对超过 600 个人类 HGSC 肿瘤的分析，确定了 Let-7i 在调节肿瘤免疫网络中的关键作用。 Let-7i 的肿瘤表达与 HGSC 患者的抗癌免疫特征呈高度正相关。证实了这一作用，在小鼠 HGSC 肿瘤中强制表达 Let-7i 导致肿瘤负荷显着减少，肿瘤中的肿瘤 T 细胞数量显着增加。与肿瘤免疫的改善相一致，Let-7i 治疗还显着增加了引流淋巴结中抗原呈递细胞 (APC) 的 CD86 表达，表明 APC 活性增强。总的来说，我们的研究结果强调了 Let-7i 在抗肿瘤免疫中的重要作用及其在 HGSC 中诱导抗肿瘤作用的潜在用途。