{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:22:43Z","timestamp":1790882563504,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T00:00:00Z","timestamp":1619827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000982","name":"Conquer Cancer Foundation","doi-asserted-by":"publisher","award":["04\/28\/18"],"award-info":[{"award-number":["04\/28\/18"]}],"id":[{"id":"10.13039\/100000982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000983","name":"Mary Kay Foundation","doi-asserted-by":"publisher","award":["05-616"],"award-info":[{"award-number":["05-616"]}],"id":[{"id":"10.13039\/100000983","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Ovarian cancer is a highly fatal malignancy characterized by early chemotherapy responsiveness but the eventual development of resistance. Immune targeting therapies are changing treatment paradigms for numerous cancer types but have had minimal success in ovarian cancer. Through retrospective patient sample analysis, we have determined that high human epididymis protein 4 (HE4) production correlates with multiple markers of immune suppression in ovarian cancer, including lower CD8+ T cell infiltration, higher PD-L1 expression, and an increase in the peripheral monocyte to lymphocyte ratio. To further understand the impact that HE4 has on the immune microenvironment in ovarian cancer, we injected rats with syngeneic HE4 high\u2013 and low\u2013expressing cancer cells and analyzed the differences in their tumor and ascites immune milieu. We found that high tumoral HE4 expression promotes an ascites cytokine profile that is rich in myeloid-recruiting and differentiation factors, with an influx of M2 macrophages and increased arginase 1 production. Additionally, CTL activation is significantly reduced in the ascites fluid, and there is a trend toward lower CTL infiltration of the tumor, whereas NK cell recruitment to the ascites and tumor is also reduced. PD-L1 expression by tumor cells and macrophages is increased by HE4 through a novel posttranscriptional mechanism. Our data have identified HE4 as a mediator of tumor-immune suppression in ovarian cancer, highlighting this molecule as a potential therapeutic target for the treatment of this devastating disease.<\/jats:p>","DOI":"10.4049\/jimmunol.2000281","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T16:40:20Z","timestamp":1619455220000},"page":"2478-2488","source":"Crossref","is-referenced-by-count":27,"title":["HE4 Overexpression by Ovarian Cancer Promotes a Suppressive Tumor Immune Microenvironment and Enhanced Tumor and Macrophage PD-L1 Expression"],"prefix":"10.1093","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8726-4628","authenticated-orcid":false,"given":"Rachael B","family":"Rowswell-Turner","sequence":"first","affiliation":[{"name":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center , Rochester, NY"},{"name":"Division of Hematology and 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NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6110-6608","authenticated-orcid":false,"given":"Ravina","family":"Pandita","sequence":"additional","affiliation":[{"name":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center , Rochester, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umayal","family":"Sivagnanalingam","sequence":"additional","affiliation":[{"name":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center , Rochester, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Hovanesian","sequence":"additional","affiliation":[{"name":"Core Research Laboratories, Rhode Island Hospital , Providence, RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole E","family":"James","sequence":"additional","affiliation":[{"name":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University , Providence, RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1685-8568","authenticated-orcid":false,"given":"Jennifer R","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University , Providence, RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sindhuja","family":"Kadambi","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, Wilmot Cancer Institute, University of Rochester Medical Center , Rochester, 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