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Patients in remission often relapse with more aggressive forms of disease within 2 years post-treatment. Alternative immuno-oncology (IO) strategies, such as immune checkpoint blockade (ICB) targeting the PD-(L)1 signaling axis, have proven inefficient so far. Our aim is to utilize epigenetic modulators to maximize the benefit of personalized IO combinations in ex vivo 3D patient-derived platforms and in vivo syngeneic models. Using patient-derived tumor ascites, we optimized an ex vivo 3D screening platform (PDOTS), which employs autologous immune cells and circulating ascites-derived tumor cells, to rapidly test personalized IO combinations. Most importantly, patient responses to platinum chemotherapy and poly-ADP ribose polymerase inhibitors in 3D platforms recapitulate clinical responses. Furthermore, similar to clinical trial results, responses to ICB in PDOTS tend to be low and positively correlated with the frequency of CD3+ immune cells and EPCAM+\/PD-L1+ tumor cells. Thus, the greatest response observed with anti-PD-1\/anti-PD-L1 immunotherapy alone is seen in patient-derived HGSOC ascites, which present with high levels of systemic CD3+ and PD-L1+ expression in immune and tumor cells, respectively. In addition, priming with epigenetic adjuvants greatly potentiates ICB in ex vivo 3D testing platforms and in vivo tumor models. We further find that epigenetic priming induces increased tumor secretion of several key cytokines known to augment T and NK cell activation and cytotoxicity, including IL-6, IP-10 (CXCL10), KC (CXCL1), and RANTES (CCL5). Moreover, epigenetic priming alone and in combination with ICB immunotherapy in patient-derived PDOTS induces rapid upregulation of CD69, a reliable early activation of immune markers in both CD4+ and CD8+ T cells. Consequently, this functional precision medicine approach could rapidly identify personalized therapeutic combinations able to potentiate ICB, which is a great advantage, especially given the current clinical difficulty of testing a high number of potential combinations in patients.<\/jats:p>","DOI":"10.3390\/cancers15164128","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T10:08:09Z","timestamp":1692180489000},"page":"4128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Thomas J.","family":"Gerton","sequence":"first","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Green","sequence":"additional","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9288-5285","authenticated-orcid":false,"given":"Marco","family":"Campisi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minyue","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iliana","family":"Gjeci","sequence":"additional","affiliation":[{"name":"Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6805-8861","authenticated-orcid":false,"given":"Navin","family":"Mahadevan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8525-9342","authenticated-orcid":false,"given":"Catherine A. A.","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Dermatopathology, Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjan","family":"Mishra","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha V.","family":"Vo","sequence":"additional","affiliation":[{"name":"Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1767-6854","authenticated-orcid":false,"given":"Koji","family":"Haratani","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6342-3324","authenticated-orcid":false,"given":"Ze-Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen T.","family":"Hasselblatt","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryanna","family":"Testino","sequence":"additional","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Connor","sequence":"additional","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine G.","family":"Lian","sequence":"additional","affiliation":[{"name":"Division of Dermatopathology, Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1502-5553","authenticated-orcid":false,"given":"Kevin M.","family":"Elias","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9510-0036","authenticated-orcid":false,"given":"Patrick","family":"Lizotte","sequence":"additional","affiliation":[{"name":"Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena V.","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Barbie","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela M.","family":"Dinulescu","sequence":"additional","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/jjco\/hyw002","article-title":"5-Hydroxymethylcytosine Expression Is Associated with Poor Survival in Cervical Squamous Cell Carcinoma","volume":"46","author":"Zhang","year":"2016","journal-title":"Jpn. 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