Brad H Nelson, Phineas T Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald Li Stevens, Shreena Kalaria, Karanvir Singh, Céline M Laumont, Elena Moss, Aliya Alimujiang, Nicola S Meagher, Adelyn Bolithon, Sian Fereday, Catherine J Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L Goode, Anthony N Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A Doherty, Holly R Harris, Kara L Cushing-Haugen, Michael S Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul Dp Pharoah, Jessica Boros, Alison H Brand, Paul R Harnett, Raghwa Sharma, Jonathan L Hecht, Naoko Sasamoto, Kathryn L Terry, Beth Y Karlan, Jenny Lester, Michael E Carney, Marc T Goodman, Brenda Y Hernandez, Lynne R Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A Fasching, Christiani Bisinotto, Francisco José Candido Dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S Cook, Nhu D Le, Aleksandra Gentry-Maharaj, Usha Menon, María J García, Cristina Rodriguez-Antona, Kyo M Farrington, Linda E Kelemen, Stefan Kommoss, Annette Staebler, Dale W Garsed, James D Brenton, Anna M Piskorz, David Dl Bowtell, Anna DeFazio, Susan J Ramus, Malcolm C Pike, Celeste Leigh Pearce
{"title":"卵巢癌长期存活者肿瘤微环境的免疫学和分子特征。","authors":"Brad H Nelson, Phineas T Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald Li Stevens, Shreena Kalaria, Karanvir Singh, Céline M Laumont, Elena Moss, Aliya Alimujiang, Nicola S Meagher, Adelyn Bolithon, Sian Fereday, Catherine J Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L Goode, Anthony N Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A Doherty, Holly R Harris, Kara L Cushing-Haugen, Michael S Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul Dp Pharoah, Jessica Boros, Alison H Brand, Paul R Harnett, Raghwa Sharma, Jonathan L Hecht, Naoko Sasamoto, Kathryn L Terry, Beth Y Karlan, Jenny Lester, Michael E Carney, Marc T Goodman, Brenda Y Hernandez, Lynne R Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A Fasching, Christiani Bisinotto, Francisco José Candido Dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S Cook, Nhu D Le, Aleksandra Gentry-Maharaj, Usha Menon, María J García, Cristina Rodriguez-Antona, Kyo M Farrington, Linda E Kelemen, Stefan Kommoss, Annette Staebler, Dale W Garsed, James D Brenton, Anna M Piskorz, David Dl Bowtell, Anna DeFazio, Susan J Ramus, Malcolm C Pike, Celeste Leigh Pearce","doi":"10.1172/JCI179501","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Funding: </strong>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.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.\",\"authors\":\"Brad H Nelson, Phineas T Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald Li Stevens, Shreena Kalaria, Karanvir Singh, Céline M Laumont, Elena Moss, Aliya Alimujiang, Nicola S Meagher, Adelyn Bolithon, Sian Fereday, Catherine J Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L Goode, Anthony N Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A Doherty, Holly R Harris, Kara L Cushing-Haugen, Michael S Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul Dp Pharoah, Jessica Boros, Alison H Brand, Paul R Harnett, Raghwa Sharma, Jonathan L Hecht, Naoko Sasamoto, Kathryn L Terry, Beth Y Karlan, Jenny Lester, Michael E Carney, Marc T Goodman, Brenda Y Hernandez, Lynne R Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A Fasching, Christiani Bisinotto, Francisco José Candido Dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S Cook, Nhu D Le, Aleksandra Gentry-Maharaj, Usha Menon, María J García, Cristina Rodriguez-Antona, Kyo M Farrington, Linda E Kelemen, Stefan Kommoss, Annette Staebler, Dale W Garsed, James D Brenton, Anna M Piskorz, David Dl Bowtell, Anna DeFazio, Susan J Ramus, Malcolm C Pike, Celeste Leigh Pearce\",\"doi\":\"10.1172/JCI179501\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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). 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引用次数: 0
摘要
背景:尽管总体预后较差,但约有15%的晚期输卵管高分化浆液性癌(HGSC)患者在接受标准治疗后可存活十年以上:尽管总体预后不佳,但仍有约 15%的晚期输卵管卵巢高级别浆液性癌(HGSC)患者在接受标准治疗后存活 10 年或更长时间:我们利用一个大型国际队列对这一特殊且研究不足的群体的肿瘤微环境进行了评估,与中期(MTS;5-7.99 年;n = 433)和短期(STS;2-4.99 年;n = 416)幸存者相比,长期幸存者(LTS;10 年以上;n = 374)更多。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、髓样细胞、PD-1+细胞和PD-L1+细胞)的上皮内和基质内密度以及上皮含量进行评分:与 STS 相比,9/10 的免疫细胞亚群与 LTS 呈正相关。尤其是上皮内 CD8+ T 细胞和间质内 B 细胞的组合,与 STS 相比,LTS 的几率增加了近五倍。所有这些关联在上皮含量高和/或C4/分化分子亚型的肿瘤中更强,尽管免疫细胞密度在上皮含量低和/或C2/免疫反应分子亚型的肿瘤中通常更高:HGSC长期存活者的肿瘤微环境具有T细胞和B细胞共同浸润、上皮细胞含量高和C4/分化分子亚型等特征,这些特征可能为免疫疗法提供新的灵感:经费来源:美国国防部(DOD)国会指导医学研究计划(CDMRP)的卵巢癌研究计划(OCRP)。Andersen 基金会;Genome 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;明尼苏达卵巢癌联盟;Ministerio de Economía y Competitividad;MRC;国家转化科学促进中心;澳大利亚国家健康与医学研究委员会 (NHMRC)、澳大利亚卵巢癌协会、Peter MacCallum 基金会、悉尼西部转化癌症研究中心、特里-福克斯研究所、夏娃呼吁(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、U.美国国立卫生研究院国家癌症研究所;VGH 和 UBC 医院基金会;维多利亚州癌症机构。
Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.
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.
期刊介绍:
The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science.
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The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.