{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T22:06:59Z","timestamp":1785535619914,"version":"3.56.0"},"reference-count":83,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2001514"],"award-info":[{"award-number":["2001514"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cervical cancer remains the fourth most common cancer affecting women worldwide, and incidences of other HPV\u2010related cancers continue to rise. For the development of effective prevention strategies in high\u2010risk patients, we aimed to better understand the roles of inflammatory pathways and the tumour microenvironment as the main driver of progression to malignancy in HPV\u2010infected tissues. We analysed the spatial organisation of seven samples of HPV+ high\u2010grade squamous intraepithelial lesion (HSIL) and cervical intraepithelial neoplasia 3 (CIN3), comparing tumour heterogeneity and immune microenvironments between premalignant (neoplastic) and adjacent cervical tissues. We observed evidence of immune suppression within the neoplastic regions across all samples and identified distinct immune clusters for each dysplastic lesion. Previous single\u2010cell data analyses in an HPV16 E7 oncoprotein\u2010driven transgenic mouse model suggested a potential role for IL34\u2010CSF1R signalling in immune modulation, where low IL34 expression was associated with Langerhans cell dysfunction, and, in cervical cancer, with poor patient outcome. Here we observed that IL34\u2010CSF1R coexpression was absent within HPV\u2010associated neoplastic regions, but present in adjacent normal tissue regions. Additionally, we identified enrichment of an M2 gene signature in neoplastic regions, while adjacent tissue was enriched with a proinflammatory M1 gene signature. Our findings provide biopathological insights into the spatial cellular and molecular mechanisms underlying HPV\u2010associated cervical cancer immune regulation and suggest a strategy to modulate the immune system in HPV\u2010positive neoplastic cervical and other tissues. \u00a9 2025 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70002","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T08:55:08Z","timestamp":1765270508000},"page":"200-214","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Spatial analysis of\n                    <scp>HPV<\/scp>\n                    \u2010associated cervical intraepithelial neoplastic tissues demonstrate distinct immune signatures associated with cervical cancer progression"],"prefix":"10.1002","volume":"268","author":[{"given":"Gianna","family":"Pavilion","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"},{"name":"QIMR Berghofer  Herston QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4337-366X","authenticated-orcid":false,"given":"Hani","family":"Vu","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"},{"name":"QIMR Berghofer  Herston QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zherui","family":"Xiong","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"},{"name":"QIMR Berghofer  Herston QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi Viet Trinh","family":"Dang","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Science The University of Queensland  Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"O'Brien","sequence":"additional","affiliation":[{"name":"Sullivan Nicolaides Pathology  Bowen Hills QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Walsh","sequence":"additional","affiliation":[{"name":"Sullivan Nicolaides Pathology  Bowen Hills QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Causer","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"},{"name":"QIMR Berghofer  Herston QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janin","family":"Chandra","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Science The University of Queensland  Woolloongabba QLD Australia"},{"name":"Dermatology Research Centre The University of Queensland  Brisbane QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-5703","authenticated-orcid":false,"given":"Quan","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"},{"name":"QIMR Berghofer  Herston QLD Australia"},{"name":"QIMRB National Centre for Spatial Tissue and AI Research QIMR Berghofer  Herston QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian H","family":"Frazer","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Science The University of Queensland  Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30072-5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(22)00501-0"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-024-00904-z"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3109\/00016489.2012.678944"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2018.06.013"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01275-09"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0204162"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34919"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.02896"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16020282"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2021.101517"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.6MA0519-172R"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1154370"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.11.001"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2360"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.MR1117-457R"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190290"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103326"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0127155"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0152886"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2019.03.1162"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.10.011"},{"key":"e_1_2_8_24_1","article-title":"CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor\u2010associated macrophages and enhancing infiltration by CD8+ T cells","volume":"2","author":"Strachan DC","year":"2013","journal-title":"Onco Targets Ther"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-023-00444-2"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202203040"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1215607"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01264-9"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.1086168"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add8977"},{"key":"e_1_2_8_31_1","unstructured":"GenomicsX.Visium Spatial Gene Expression for FFPE: Tissue Preparation Imaging and Decrosslinking (Demonstrated Protocol) 2022. [Available from:https:\/\/www.10xgenomics.com\/support; Accessed December 2022]."},{"key":"e_1_2_8_32_1","unstructured":"AkoyaB.Opal Multiplex Immunohistochemistry Assay User Manual (FP1487001KT\u2013FP1497001KT) 2021. [Available from:https:\/\/www.akoyabio.com; Accessed December 2023]."},{"key":"e_1_2_8_33_1","unstructured":"Illumina.bcl2fastq Conversion Software v2.20 User Guide 2017."},{"key":"e_1_2_8_34_1","unstructured":"GenomicsX.Space Ranger v2.0 User Guide 2023. [Available from:https:\/\/www.10xgenomics.com\/support\/software\/space-ranger; Accessed June 2023]."},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1874-1"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw777"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/database\/baz046"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.90"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaf018"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0501"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13067"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2005.01.011"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01471-y"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/tropicalmed9010013"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0297872"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0302-5"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200421140"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43120-6"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0969-x"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1219"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1052457"},{"key":"e_1_2_8_56_1","doi-asserted-by":"crossref","unstructured":"HockeyL MulayO XiongZ.MMCCI: multimodal integrative analysis of single\u2010cell and spatial cell\u2010type communications to uncover overarching and condition\u2010specific ligand\u2010receptor interaction pathways bioRxiv; 2024. [Not peer reviewed].","DOI":"10.1101\/2024.02.28.582639"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-8258(02)00070-7"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-009552"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01177-w"},{"key":"e_1_2_8_60_1","volume-title":"The Role of IL34 in HPV\u2010Mediated Epithelial Cancers","author":"Dang TVT","year":"2025"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.70018"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2025.05.003"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12253-016-0094-1"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1309\/AJCPQQ07WUTZUTES"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10092245"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17622-5"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-018-0721-x"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4210"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-00619-0"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46785-9"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2012.159"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-021-08412-4"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1539317"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI163841"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2008.101"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1155\/2008\/298495"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.060501"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15123125"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.09.138"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12113269"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.006226"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1099696"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-018-0060-2"},{"key":"e_1_2_8_84_1","doi-asserted-by":"crossref","unstructured":"PrakrithiP GriceLF ZhangF et al.Integrating 12 spatial and single cell technologies to characterise tumour Neighbourhoods and cellular interactions in three skin cancer types.bioRxiv2025; 2025.07.25.666708. [Not peer reviewed].","DOI":"10.1101\/2025.07.25.666708"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.70002","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.70002","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.70002","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T11:59:17Z","timestamp":1769774357000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.70002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,9]]},"references-count":83,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/path.70002"],"URL":"https:\/\/doi.org\/10.1002\/path.70002","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,9]]},"assertion":[{"value":"2024-11-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}