BACKGROUND Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment. METHODS We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content. RESULTS Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSIONS The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

中文翻译：

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卵巢癌长期幸存者肿瘤微环境的免疫学和分子学特征。


背景 尽管总体预后不佳，但约 15% 的晚期输卵管卵巢高级别浆液性癌 （HGSC） 患者在标准治疗后存活了 10 年或更长时间。方法 我们评估了这个特殊的、研究不足的群体的肿瘤微环境，使用一个大型国际队列，该队列富含长期幸存者 （LTS;10+ 岁;n = 374） 与中期 （MTS;5-7.99 岁;n = 433） 和短期幸存者 （STS;2-4.99 岁;n = 416）。对原发肿瘤样本进行免疫染色，并对 10 个免疫细胞亚群 （包括 T 细胞、 B 细胞、浆细胞、髓系细胞、PD-1+ 细胞和 PD-L1+ 细胞） 的上皮内和基质内密度和上皮含量进行评分。结果 与 STS 相比，9/10 的免疫细胞亚群与 LTS 呈正相关。特别是，与 STS 相比，上皮内 CD8+ T 细胞和基质内 B 细胞的组合显示 LTS 的几率增加了近 5 倍。所有这些关联在高上皮含量和/或 C4/分化分子亚型的肿瘤中更强，尽管免疫细胞密度在低上皮含量和/或 C2/免疫反应分子亚型的肿瘤中通常较高。结论 HGSC 长期幸存者的肿瘤微环境以 T 细胞和 B 细胞共浸润、高上皮含量和 C4/分化分子亚型的交集为特征，这些特征可能激发免疫治疗的新方法。资助美国国会指导医学研究计划 （CDMRP） 的卵巢癌研究计划 （OCRP） 国防部 （DOD）;美国癌症协会;卑诗癌症基金会;加拿大卓越中心网络;加拿大癌症协会;加拿大卫生研究院;新南威尔士州、维多利亚州、昆士兰州、南澳大利亚州和塔斯马尼亚州癌症委员会、西澳大利亚癌症基金会;新南威尔士州癌症研究所;英国癌症研究中心;Deutsche Forschungsgesellschaft;埃尔朗根-纽伦堡大学的 ELAN 基金;Fred C. 和 Katherine B. Andersen 基金会;基因组 BC;德国癌症研究中心;德国联邦教育与研究部，临床生物医学研究计划;卡洛斯三世健康研究所;梅奥基金会;明尼苏达州卵巢癌联盟;Ministerio de Economía y Competitividad;MRC;国家促进转化科学中心;澳大利亚国家健康与医学研究委员会 （NHMRC）;澳大利亚卵巢癌;彼得麦卡勒姆基金会;Sydney West 转化癌症研究中心;特里福克斯研究所;The Eve Appeal（橡树基金会）;剑桥大学英国国家健康研究所生物医学研究中心;匹兹堡大学医学院;美国国立卫生研究院美国国家癌症研究所;VGH & UBC 医院基金会;维多利亚癌症机构。