{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:58:17Z","timestamp":1791917897503,"version":"4.3.4"},"reference-count":103,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T00:00:00Z","timestamp":1694908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009326","name":"Cancer Research Society","doi-asserted-by":"publisher","award":["25510"],"award-info":[{"award-number":["25510"]}],"id":[{"id":"10.13039\/100009326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000032","name":"Institute of Infection and Immunity","doi-asserted-by":"publisher","award":["148442"],"award-info":[{"award-number":["148442"]}],"id":[{"id":"10.13039\/501100000032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:p>Human papillomavirus (HPV)\u2010associated cancer continues to evade the immune system by promoting a suppressive tumor microenvironment. Therefore, immunotherapy appears to be a promising approach for targeting HPV\u2010associated tumors. We hypothesized that valproic acid (VA) as an epigenetic agent combined with avelumab may enhance the antitumor immunity in HPV\u2010associated solid tumors. We performed bulk RNA\u2010sequencing (RNA\u2010Seq) on total peripheral blood mononuclear cells (PBMCs) of seven nonresponders (NRs) and four responders (Rs). A total of 39 samples (e.g., pretreatment, post\u2010VA, postavelumab, and endpoint) were analyzed. Also, we quantified plasma analytes and performed flow cytometry. We observed a differential pattern in immune response following treatment with VA and\/or avelumab in NRs vs. Rs. A significant upregulation of transcripts associated with NETosis [the formation of neutrophil extracellular traps (NETs)] and neutrophil degranulation pathways was linked to the presence of a myeloid\u2010derived suppressor cell signature in NRs. We noted the elevation of IL\u20108\/IL\u201018 cytokines and a distinct transcriptome signature at the baseline and endpoint in NRs. By using the receiver operator characteristics, we identified a cutoff value for the plasma IL\u20108\/IL\u201018 to discriminate NRs from Rs. We found differential therapeutic effects for VA and avelumab in NRs vs. Rs. Thus, our results imply that measuring the plasma IL\u20108\/IL\u201018 and bulk RNA\u2010Seq of PBMCs may serve as valuable biomarkers to predict immunotherapy outcomes.<\/jats:p>","DOI":"10.1002\/1878-0261.13519","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T04:30:43Z","timestamp":1694147443000},"page":"1209-1230","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transcriptomic profiling of peripheral blood cells in\n                    <scp>HPV<\/scp>\n                    \u2010associated carcinoma patients receiving combined valproic acid and avelumab"],"prefix":"10.1002","volume":"18","author":[{"given":"Najmeh","family":"Bozorgmehr","sequence":"first","affiliation":[{"name":"Division of Foundational Sciences, School of Dentistry University of Alberta  Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussain","family":"Syed","sequence":"additional","affiliation":[{"name":"Division of Foundational Sciences, School of Dentistry University of Alberta  Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siavash","family":"Mashhouri","sequence":"additional","affiliation":[{"name":"Division of Foundational Sciences, School of Dentistry University of Alberta  Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology University of Alberta  Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-2009","authenticated-orcid":false,"given":"Shokrollah","family":"Elahi","sequence":"additional","affiliation":[{"name":"Division of Foundational Sciences, School of Dentistry University of Alberta  Edmonton AB Canada"},{"name":"Department of Medical Oncology University of Alberta  Edmonton AB Canada"},{"name":"Faculty of Medicine and Dentistry Li Ka Shing Institute of Virology University of Alberta  Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,17]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3175"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0205-5"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.02.003"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1320753111"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.01.003"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.06.081"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01215"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0306-5"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-018-0333-1"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002371-200111000-00001"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12150"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00783"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.754196"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2018.10.004"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00603-7"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-019-0743-4"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13235889"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-023-01050-x"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0348-4"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2017.6102"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/v10020082"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.910486"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-01636-x"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2007.11.003"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00092"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2008.09.008"},{"key":"e_1_2_11_29_1","first-page":"97","article-title":"Induction of differentiation and suppression of malignant phenotype of human neuroblastoma BE(2)\u2010C cells by valproic acid: enhancement by combination with interferon\u2010alpha","volume":"20","author":"Cinatl J","year":"2002","journal-title":"Int J Oncol"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-2126(01)00151-5"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2016.3508"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-4-55"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/9678098"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001849"},{"key":"e_1_2_11_35_1","unstructured":"AHS Cancer Control Alberta.The LATENT trial: lytic activation to enhance Neoantigen\u2010directed therapy a study to evaluate the feasibility and efficacy of the combined use of Avelumab with Valproic acid for the treatment of virus\u2010associated cancer. clinicaltrials.gov; 2019 Jul. Report No.: NCT03357757 [cited 2022 Mar 30]. Available from:https:\/\/clinicaltrialsgov\/ct2\/show\/NCT03357757"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30074-8"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1289"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010014\u20100550\u20108"},{"key":"e_1_2_11_39_1","unstructured":"KoldeR.pheatmap: Pretty Heatmaps.2019[cited 2023 Jul 20]. Available from:https:\/\/cran.r\u2010project.org\/web\/packages\/pheatmap\/index.html"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-24277-4"},{"key":"e_1_2_11_41_1","unstructured":"ggplot2 citation info. [cited 2023 Jul 20]. Available from:https:\/\/cran.r\u2010project.org\/web\/packages\/ggplot2\/citation.html"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt703"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0114-2"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbab265"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002189"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40164-023-00375-5"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01793"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17090-y"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0208100"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-006595"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/38664"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-051113-024537"},{"issue":"165","key":"e_1_2_11_54_1","first-page":"5269","article-title":"The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine\u2010induced angiogenic activity","volume":"2000","author":"Addison CL","year":"1950","journal-title":"J Immunol"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-018-1710-1"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphs.2018.06.014"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.129353"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.50.29682"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00630-3"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-019-0151-0"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01245-8"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02767-19"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.705197"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00779-x"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00588-9"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00384-21"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139598"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176009"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol_00000129"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8121647"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1177\/1559325820931360"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2627-5"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.575175"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.05.003"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.931630"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.02.007"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201015\u20102463"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00490-y"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12876\u2010018\u20100877\u20109"},{"key":"e_1_2_11_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2006.04.002"},{"key":"e_1_2_11_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0856-x"},{"key":"e_1_2_11_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0860-1"},{"key":"e_1_2_11_83_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm-20-1513"},{"key":"e_1_2_11_84_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000901"},{"key":"e_1_2_11_85_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01223"},{"key":"e_1_2_11_86_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01676"},{"key":"e_1_2_11_87_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.150735"},{"key":"e_1_2_11_88_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0248639"},{"key":"e_1_2_11_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2017.03.002"},{"key":"e_1_2_11_90_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901481"},{"key":"e_1_2_11_91_1","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.1900087"},{"key":"e_1_2_11_92_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2394-6"},{"key":"e_1_2_11_93_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010cancerbio\u2010080421\u2010015537"},{"key":"e_1_2_11_94_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-2903"},{"key":"e_1_2_11_95_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02588-7"},{"key":"e_1_2_11_96_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.747863"},{"key":"e_1_2_11_97_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.356584"},{"key":"e_1_2_11_98_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.690207"},{"key":"e_1_2_11_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.11.155"},{"key":"e_1_2_11_100_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0312145"},{"key":"e_1_2_11_101_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.757238"},{"key":"e_1_2_11_102_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131916"},{"key":"e_1_2_11_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2021.104301"},{"key":"e_1_2_11_104_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.243063"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.13519","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T01:38:41Z","timestamp":1715132321000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.13519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,17]]},"references-count":103,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1002\/1878-0261.13519"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.13519","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/1878-0261.13519\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.13519\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.13519\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.13519\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.13519\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.13519\/v1\/decision1","asserted-by":"object"}]},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,17]]},"assertion":[{"value":"2023-05-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}