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Sperm\u2010specific proteins aberrantly expressed in cancer, known as cancer\u2010testis antigens (CTAs), are often pursued as cancer biomarkers and therapeutic targets based on the assumption they are neoantigens absent from the circulation in healthy men. Here, we identify a wide range of germ cell\u2010derived and sperm\u2010specific proteins, including multiple CTAs, that are selectively deposited by the Sertoli cells of the adult mouse and human seminiferous tubules into testicular interstitial fluid (TIF) that is \u201coutside\u201d the blood\u2010testis barrier. From TIF, the proteins can access the circulatory\u2010 and immune systems. Disruption of spermatogenesis decreases the abundance of these proteins in mouse TIF, and a sperm\u2010specific CTA is significantly decreased in TIF from infertile men, suggesting that exposure of certain CTAs to the immune system could depend on fertility status. The results provide a rationale for the development of blood\u2010based tests useful in the management of male infertility and indicate CTA candidates for cancer immunotherapy and biomarker development that could show sex\u2010specific and male\u2010fertility\u2010related responses.<\/jats:p>","DOI":"10.1096\/fj.202002484r","type":"journal-article","created":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T22:08:28Z","timestamp":1612994908000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Sperm proteins and cancer\u2010testis antigens are released by the seminiferous tubules in mice and men"],"prefix":"10.1096","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-6136","authenticated-orcid":false,"given":"Liza","family":"O'Donnell","sequence":"first","affiliation":[{"name":"Hudson Institute of Medical Research Clayton VIC Australia"},{"name":"Department of Molecular and Translational Sciences Monash University Clayton VIC Australia"},{"name":"Faculty of Science The University of Newcastle Callaghan NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Rebourcet","sequence":"additional","affiliation":[{"name":"Faculty of Science The University of Newcastle Callaghan NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura F.","family":"Dagley","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raouda","family":"Sgaier","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research Clayton VIC Australia"},{"name":"Department of Molecular and Translational Sciences Monash University Clayton VIC Australia"},{"name":"Department of Urology, Pediatric Urology and Andrology Medical Faculty Justus\u2010Liebig\u2010University Giessen UKGM GmbH Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Infusini","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"O'Shaughnessy","sequence":"additional","affiliation":[{"name":"Univ Rennes Inserm EHESP Irset (Institut de recherche en sant\u00e9, environnement et travail) \u2010 UMR_S 1085 Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Chalmel","sequence":"additional","affiliation":[{"name":"Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail), UMR_S 1085 University Rennes Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Fietz","sequence":"additional","affiliation":[{"name":"Institute for Veterinary Anatomy, Histology and Embryology Justus\u2010Liebig\u2010University Giessen Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Weidner","sequence":"additional","affiliation":[{"name":"Department of Urology, Pediatric Urology and Andrology Medical Faculty Justus\u2010Liebig\u2010University Giessen UKGM GmbH Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien M. 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