{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:11:43Z","timestamp":1792192303491,"version":"4.4.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","award":["K43TW011095"],"award-info":[{"award-number":["K43TW011095"]}],"id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and\/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and\/or how HIV and\/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV<jats:sup>+<\/jats:sup>, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV<jats:sup>-<\/jats:sup> participants than HIV<jats:sup>+<\/jats:sup> participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3<jats:sup>+<\/jats:sup> cells (p = 0.02), CD68<jats:sup>+<\/jats:sup> cells (p = 0.01), CD163<jats:sup>+<\/jats:sup> cells (p = 0.01), LAG3<jats:sup>+<\/jats:sup> cells (p = 0.01), PD1<jats:sup>+<\/jats:sup> cells (p = 0.01) and TIM3<jats:sup>+<\/jats:sup> cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (\u2374 = 0.69; p = 0.0001), PD1 and TIM3 (\u2374 = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (\u2374 = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.<\/jats:p>","DOI":"10.1371\/journal.pone.0300729","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T17:25:42Z","timestamp":1714584342000},"page":"e0300729","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["The effects of HIV and oncogenic human papillomavirus on the tumor immune microenvironment of penile squamous cell 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Brady","year":"2013","journal-title":"Dermatol Surg"},{"key":"pone.0300729.ref003","first-page":"e117","article-title":"Incidence of penile cancer worldwide: systematic review and meta-analysis","volume":"41","author":"CE Montes Cardona","year":"2017","journal-title":"Rev Panam Salud Publica"},{"issue":"2","key":"pone.0300729.ref004","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/MOU.0000000000000581","article-title":"Penile cancer epidemiology and risk factors: a contemporary review","volume":"29","author":"A Douglawi","year":"2019","journal-title":"Curr Opin Urol"},{"issue":"5","key":"pone.0300729.ref005","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1590\/S1677-55382008000500007","article-title":"Epidemiologic study on penile cancer in Brazil.","volume":"34","author":"LA Favorito","year":"2008","journal-title":"Int Braz J 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(Basel)."},{"key":"pone.0300729.ref009","doi-asserted-by":"crossref","first-page":"1785428","DOI":"10.1155\/2019\/1785428","article-title":"Management of Advanced and Metastatic Prostate Cancer: A Need for a Sub-Saharan Guideline.","volume":"2019","author":"A Cassell","year":"2019","journal-title":"J Oncol"},{"issue":"4","key":"pone.0300729.ref010","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1177\/09564624221148622","article-title":"The association between penile cancer and HIV infection: A literature review","volume":"34","author":"AP Amini","year":"2023","journal-title":"Int J STD AIDS"},{"issue":"4","key":"pone.0300729.ref011","doi-asserted-by":"crossref","first-page":"295 e1","DOI":"10.1016\/j.urolonc.2018.12.003","article-title":"Penile cancer\u2014Incidence, mortality, and survival in Saxony, Germany.","volume":"37","author":"O Schoffer","year":"2019","journal-title":"Urol 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Steck SW","year":"2021","journal-title":"Current Problems in Cancer: Case Reports."},{"issue":"1","key":"pone.0300729.ref018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000518758","article-title":"Human Immunodeficiency Virus Infection Promotes Human Papillomavirus-Mediated Anal Squamous Carcinogenesis: An Immunologic and Pathobiologic Review.","volume":"89","author":"O Bushara","year":"2022","journal-title":"Pathobiology"},{"issue":"1","key":"pone.0300729.ref019","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1097\/PAI.0000000000000605","article-title":"Development of a Diagnostic Programmed Cell Death 1-Ligand 1 Immunohistochemistry Assay for Nivolumab Therapy in Melanoma.","volume":"26","author":"T Phillips","year":"2018","journal-title":"Appl Immunohistochem Mol Morphol."},{"key":"pone.0300729.ref020","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.3389\/fonc.2020.01521","article-title":"Importance of HPV in Chinese Penile Cancer: A Contemporary Multicenter Study.","volume":"10","author":"W Gu","year":"2020","journal-title":"Front Oncol"},{"key":"pone.0300729.ref021","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s12894-015-0101-y","article-title":"Cancer of the penis associated with HIV: a report of three cases presenting at the CHU cocody, ivory coast.","volume":"15","author":"PG Konan","year":"2015","journal-title":"BMC Urol."},{"issue":"5","key":"pone.0300729.ref022","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1002\/ijc.21961","article-title":"Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival","volume":"119","author":"AP Lont","year":"2006","journal-title":"Int J Cancer"},{"issue":"3","key":"pone.0300729.ref023","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1093\/annonc\/mdf024","article-title":"An explosive course of squamous cell penile cancer in an AIDS patient","volume":"13","author":"C Theodore","year":"2002","journal-title":"Ann Oncol"},{"issue":"7","key":"pone.0300729.ref024","doi-asserted-by":"crossref","first-page":"e80","DOI":"10.1097\/PAS.0000000000001477","article-title":"Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers V: Recommendations on the Use of Immunohistochemical and Molecular Biomarkers in Penile Cancer.","volume":"44","author":"S Canete-Portillo","year":"2020","journal-title":"Am J Surg Pathol"},{"key":"pone.0300729.ref025","doi-asserted-by":"crossref","first-page":"16086","DOI":"10.1038\/nrdp.2016.86","article-title":"Carcinogenic human papillomavirus infection.","volume":"2","author":"M Schiffman","year":"2016","journal-title":"Nat Rev Dis Primers"},{"issue":"14","key":"pone.0300729.ref026","doi-asserted-by":"crossref","DOI":"10.3390\/cancers15143713","article-title":"The Prognostic Role of Human Papillomavirus and p16 Status in Penile Squamous Cell Carcinoma-A Systematic Review.","volume":"15","author":"K Parza","year":"2023","journal-title":"Cancers (Basel)."},{"issue":"4","key":"pone.0300729.ref027","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1590\/S1677-55382008000400009","article-title":"Human papillomavirus and penile cancers in Rio de Janeiro, Brazil: HPV typing and clinical features","volume":"34","author":"MA Scheiner","year":"2008","journal-title":"Int Braz J Urol"},{"issue":"4","key":"pone.0300729.ref028","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.21037\/tcr.2020.02.41","article-title":"Higher T cell immunoglobulin mucin-3 (Tim-3) expression in cervical cancer is associated with a satisfactory prognosis.","volume":"9","author":"Y Wang","year":"2020","journal-title":"Transl Cancer Res"},{"issue":"3","key":"pone.0300729.ref029","doi-asserted-by":"crossref","first-page":"e21401","DOI":"10.1096\/fj.202000528RR","article-title":"The role of Tim-3\/Galectin-9 pathway in T-cell function and prognosis of patients with human papilloma virus-associated cervical carcinoma","volume":"35","author":"Z Chen","year":"2021","journal-title":"FASEB J"},{"issue":"1","key":"pone.0300729.ref030","doi-asserted-by":"crossref","first-page":"e53834","DOI":"10.1371\/journal.pone.0053834","article-title":"Tim-3 expression in cervical cancer promotes tumor metastasis","volume":"8","author":"Y Cao","year":"2013","journal-title":"PLoS One"},{"issue":"1","key":"pone.0300729.ref031","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12935-021-02407-8","article-title":"Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier.","volume":"22","author":"S Vafaei","year":"2022","journal-title":"Cancer Cell Int"},{"key":"pone.0300729.ref032","doi-asserted-by":"crossref","first-page":"731175","DOI":"10.3389\/fonc.2021.731175","article-title":"Targeting Tim-3 in Cancer With Resistance to PD-1\/PD-L1 Blockade.","volume":"11","author":"T Tian","year":"2021","journal-title":"Front Oncol."},{"issue":"10","key":"pone.0300729.ref033","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1084\/jem.20100643","article-title":"Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity","volume":"207","author":"K Sakuishi","year":"2010","journal-title":"J Exp Med"},{"issue":"6","key":"pone.0300729.ref034","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1590\/s1677-5538.ibju.2015.0416","article-title":"Tumor histologic grade is the most important prognostic factor in patients with penile cancer and clinically negative lymph nodes not submitted to regional lymphadenectomy","volume":"42","author":"GA Aita","year":"2016","journal-title":"Int Braz J Urol"},{"issue":"6","key":"pone.0300729.ref035","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1001\/jamaoto.2022.0640","article-title":"Tumor Histological Grade and Immunotherapy Response in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.","volume":"148","author":"HH Alkhatib","year":"2022","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"issue":"22","key":"pone.0300729.ref036","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1093\/jnci\/87.22.1705","article-title":"Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma","volume":"87","author":"L Gregoire","year":"1995","journal-title":"J Natl Cancer Inst"},{"issue":"4","key":"pone.0300729.ref037","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s11515-018-1513-3","article-title":"Metastatic tumor cells\u2014genotypes and phenotypes.","volume":"13","author":"D Gao","year":"2018","journal-title":"Front Biol (Beijing)."},{"issue":"11","key":"pone.0300729.ref038","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.1093\/annonc\/mdy399","article-title":"Immunological differences between primary and metastatic breast cancer","volume":"29","author":"B Szekely","year":"2018","journal-title":"Ann Oncol"},{"issue":"6","key":"pone.0300729.ref039","doi-asserted-by":"crossref","first-page":"e1153208","DOI":"10.1080\/2162402X.2016.1153208","article-title":"Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases","volume":"5","author":"B Sobottka","year":"2016","journal-title":"Oncoimmunology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0300729","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T17:25:56Z","timestamp":1714584356000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0300729"}},"subtitle":[],"editor":[{"given":"Kekeli Kodjo","family":"Adanu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,5,1]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0300729","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,1]]}}}