{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:55:02Z","timestamp":1785840902278,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,4]]},"group-title":"Cancer Biology","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["HL170193"],"award-info":[{"award-number":["HL170193"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["P20 GM121327"],"award-info":[{"award-number":["P20 GM121327"]}]},{"name":"National Cancer Institute","award":["R01 CA237643"],"award-info":[{"award-number":["R01 CA237643"]}]},{"name":"National Cancer Institute","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"National Cancer Institute","award":["T32 CA165990"],"award-info":[{"award-number":["T32 CA165990"]}]},{"name":"National Cancer Institute","award":["K99 CA303792"],"award-info":[{"award-number":["K99 CA303792"]}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"crossref","award":["UL1 TR001998"],"award-info":[{"award-number":["UL1 TR001998"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["133123-RSG-19-081-01-TBG"],"award-info":[{"award-number":["133123-RSG-19-081-01-TBG"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["IRG-19-140-31"],"award-info":[{"award-number":["IRG-19-140-31"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Squamous cell carcinoma of the lung is a difficult-to-treat cancer with high prevalence in the US, and particularly in Kentucky. Here, we sought to test if the EZH1\/2 inhibitor valemetostat improves anti-PD1 responses in squamous cell lung cancer models, and to develop ex vivo models to test immunotherapy drug combinations. We found that valemetostat augmented anti-tumor responses to anti-PD1 therapy, led to up-regulation of tumor cell specific Major Histocompatibility Complex Class II (MHC Class II), and drove systemic neutrophil maturation. Likewise,\n                  <jats:italic>Ezh2<\/jats:italic>\n                  knock-out mice produced neutrophils that were more apoptotic, less migratory, and less able to produce extracellular nets, but had similar ability to kill bacteria as\n                  <jats:italic>Ezh2<\/jats:italic>\n                  -WT neutrophils. To test tumor responses to differing neutrophil populations, we engineered three-dimensional air-liquid interface cultures with tumoroids, lung mesenchymal cells, and T cells, with and without bone marrow containing neutrophils and myeloid progenitors from distinct donors. Bone marrow from tumor-na\u00efve or mice with actively growing untreated tumors boosted tumoroid growth, while bone marrow from spontaneously tumor-rejected or mice with tumors treated with valemetostat was anti-tumor. MHC Class II blockade lowered the ability of bone marrow to boost tumor growth, and reduced the ability of valemetostat with anti-PD1 to reduce tumoroid growth. Patient samples revealed a strong negative correlation between EZH2 and MHC Class II, suggesting that targeting EZH2 activity could lead to marked increase in MHC Class II and improve treatment responses in lung squamous cell carcinomas.\n                <\/jats:p>","DOI":"10.64898\/2026.06.01.725956","type":"posted-content","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:15Z","timestamp":1780617615000},"source":"Crossref","is-referenced-by-count":0,"title":["EZH1\/2 inhibition improves immunotherapy response through MHC Class II de-repression and neutrophil reprogramming"],"prefix":"10.64898","author":[{"given":"Avery R.","family":"Childress","sequence":"first","affiliation":[{"name":"Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave-Preston","family":"Esoe","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiulong","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christain M.","family":"Gosser","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yindan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Plaugher","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY, United 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