{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T13:21:41Z","timestamp":1775827301842,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["NCI HHS N2612015000381"],"award-info":[{"award-number":["NCI HHS N2612015000381"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Our previous preclinical studies demonstrated that non\u2010steroidal anti\u2010inflammatory drugs (NSAIDs) such as aspirin and naproxen significantly inhibited prostate tumorigenesis in a\n                    <jats:italic>TMPRSS2\u2010ERG<\/jats:italic>\n                    fusion\u2010driven model compared to non\u2010fusion models. Since\n                    <jats:italic>TMPRSS2\u2010ERG<\/jats:italic>\n                    fusion\u2010positive tumors display heightened inflammatory signaling and substantial immune infiltration, we hypothesized that the differential efficacy of NSAIDs may arise from their ability to remodel the tumor immune microenvironment. Accordingly, in the present study, we systematically profiled innate and adaptive immune\u2010cell populations: F4\/80\u207a macrophages, mast cells, neutrophils, CD3\u207a T cells, CD8\u207a cytotoxic T cells, FoxP3\u207a regulatory T cells, CD20\u207a B cells, IgKC\u207a plasma cells, and Granzyme B\u207a effector cells in highly infiltrated dorso\u2010lateral prostate regions of\n                    <jats:italic>TMPRSS2\u2010ERG<\/jats:italic>\n                    fusion\u2010driven and non\u2010fusion PCa models, with and without NSAID intervention. Our analyses revealed pronounced macrophage infiltration in\n                    <jats:italic>TMPRSS2\u2010ERG. Pten<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>flox\/flox<\/jats:italic>\n                    <\/jats:sup>\n                    and Hi\u2010Myc\n                    <jats:sup>+\/<\/jats:sup>\n                    <jats:sup>\u2212<\/jats:sup>\n                    model, which was further augmented by NSAIDs. Importantly, NSAID intervention shifted macrophage polarization toward an M1\u2010like, pro\u2010inflammatory state, contrasting with the M2\u2010dominant phenotype characteristic of untreated tumors. NSAID treatment reduced mast cell density within the stromal compartment, suggesting suppression of mast cell\u2010mediated tumor\u2010promoting signals. In the fusion model, infiltration of total T cells and CD8\u207a cytotoxic T cells decreased following NSAID exposure, whereas FoxP3\u207a Tregs remained largely unaffected. Both models showed increased B\u2010cell infiltration independent of NSAID efficacy, and no clear correlation was observed between plasma\u2010cell presence and treatment response. Collectively, our findings offer new insight into NSAID\u2010mediated immunomodulation in\n                    <jats:italic>TMPRSS2\u2010ERG<\/jats:italic>\n                    fusion\u2010driven PCa; however, further in\u2010depth immune subtyping and spatial mapping could fully delineate the immunological mechanisms driving NSAID responsiveness.\n                  <\/jats:p>","DOI":"10.1002\/mc.70099","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T09:46:39Z","timestamp":1772963199000},"page":"589-602","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Tumor Infiltrating Immune Cell Profiles in Mice by Non\u2010Steroidal Anti\u2010Inflammatory Drugs (Aspirin and Naproxen) During\n                    <i>TMPRSS2\u2010ERG<\/i>\n                    (Fusion)\u2010Driven and Non\u2010Fusion Driven Prostate Cancer"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9792-5936","authenticated-orcid":false,"given":"Munendra Singh","family":"Tomar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0371-1070","authenticated-orcid":false,"given":"Komal","family":"Raina","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora Colorado USA"},{"name":"Department of Pharmaceutical Sciences South Dakota State University Brookings South Dakota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0725-5148","authenticated-orcid":false,"given":"Neha","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0550-1467","authenticated-orcid":false,"given":"Rama","family":"Kant","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer T.","family":"Fox","sequence":"additional","affiliation":[{"name":"Chemopreventive Agent Development Research Group, Division of Cancer Prevention National Cancer Institute, NIH Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chapla","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9455-0235","authenticated-orcid":false,"given":"Rajesh","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora Colorado USA"},{"name":"University of Colorado Cancer Center University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.70028"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000541881"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2402"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.4172\/1948-5956.1000119"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1117679"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwq175"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/pcan.2015.49"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1186"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15205054"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.23718"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2014.271"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/436123"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2022.07.002"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1252"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-025-02243-8"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5VMR1116-491RR"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-022-02085-x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2019.07.007"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2022.2027904"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a030627"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0161084"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.23413"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00197-1"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2025.0149"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-025-06519-x"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.37349\/etat.2022.00108"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-17-0276"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15406-5"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2014.02.020"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-012-1276-7"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-018-0083-x"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2017.167"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.613"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.11.030"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.11.019"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.14735\/amko2018421"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2020.02.012"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.70099","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mc.70099","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.70099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T12:10:36Z","timestamp":1775823036000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.70099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":38,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/mc.70099"],"URL":"https:\/\/doi.org\/10.1002\/mc.70099","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]},"assertion":[{"value":"2026-01-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}