Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells
High-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. 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)...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/16/4128 |
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| author | Thomas J. Gerton Allen Green Marco Campisi Minyue Chen Iliana Gjeci Navin Mahadevan Catherine A. A. Lee Ranjan Mishra Ha V. Vo Koji Haratani Ze-Hua Li Kathleen T. Hasselblatt Bryanna Testino Trevor Connor Christine G. Lian Kevin M. Elias Patrick Lizotte Elena V. Ivanova David A. Barbie Daniela M. Dinulescu |
| author_facet | Thomas J. Gerton Allen Green Marco Campisi Minyue Chen Iliana Gjeci Navin Mahadevan Catherine A. A. Lee Ranjan Mishra Ha V. Vo Koji Haratani Ze-Hua Li Kathleen T. Hasselblatt Bryanna Testino Trevor Connor Christine G. Lian Kevin M. Elias Patrick Lizotte Elena V. Ivanova David A. Barbie Daniela M. Dinulescu |
| author_sort | Thomas J. Gerton |
| collection | DOAJ |
| description | High-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. 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. |
| first_indexed | 2024-03-11T00:03:55Z |
| format | Article |
| id | doaj.art-e89b6dbfe788429b935d38f995f8d03c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T00:03:55Z |
| publishDate | 2023-08-01 |
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| series | Cancers |
| spelling | doaj.art-e89b6dbfe788429b935d38f995f8d03c2023-11-19T00:33:39ZengMDPI AGCancers2072-66942023-08-011516412810.3390/cancers15164128Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor CellsThomas J. Gerton0Allen Green1Marco Campisi2Minyue Chen3Iliana Gjeci4Navin Mahadevan5Catherine A. A. Lee6Ranjan Mishra7Ha V. Vo8Koji Haratani9Ze-Hua Li10Kathleen T. Hasselblatt11Bryanna Testino12Trevor Connor13Christine G. Lian14Kevin M. Elias15Patrick Lizotte16Elena V. Ivanova17David A. Barbie18Daniela M. Dinulescu19Division of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USABelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADivision of Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USAWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USABelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USABelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USABelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADivision of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USAHigh-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. 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.https://www.mdpi.com/2072-6694/15/16/4128PDOTSovarian cancerascitesepigeneticmethylationICB |
| spellingShingle | Thomas J. Gerton Allen Green Marco Campisi Minyue Chen Iliana Gjeci Navin Mahadevan Catherine A. A. Lee Ranjan Mishra Ha V. Vo Koji Haratani Ze-Hua Li Kathleen T. Hasselblatt Bryanna Testino Trevor Connor Christine G. Lian Kevin M. Elias Patrick Lizotte Elena V. Ivanova David A. Barbie Daniela M. Dinulescu Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells Cancers PDOTS ovarian cancer ascites epigenetic methylation ICB |
| title | Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells |
| title_full | Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells |
| title_fullStr | Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells |
| title_full_unstemmed | Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells |
| title_short | Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells |
| title_sort | development of a patient derived 3d immuno oncology platform to potentiate immunotherapy responses in ascites derived circulating tumor cells |
| topic | PDOTS ovarian cancer ascites epigenetic methylation ICB |
| url | https://www.mdpi.com/2072-6694/15/16/4128 |
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