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 |
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Multidisciplinary Digital Publishing Institute
2023
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| Online Access: | https://hdl.handle.net/1721.1/152071 |
| _version_ | 1811096438365487104 |
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| author | Gerton, Thomas J. Green, Allen Campisi, Marco Chen, Minyue Gjeci, Iliana Mahadevan, Navin Lee, Catherine A. A. Mishra, Ranjan Vo, Ha V. Haratani, Koji Li, Ze-Hua Hasselblatt, Kathleen T. Testino, Bryanna Connor, Trevor Lian, Christine G. Elias, Kevin M. Lizotte, Patrick Ivanova, Elena V. Barbie, David A. Dinulescu, Daniela M. |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Gerton, Thomas J. Green, Allen Campisi, Marco Chen, Minyue Gjeci, Iliana Mahadevan, Navin Lee, Catherine A. A. Mishra, Ranjan Vo, Ha V. Haratani, Koji Li, Ze-Hua Hasselblatt, Kathleen T. Testino, Bryanna Connor, Trevor Lian, Christine G. Elias, Kevin M. Lizotte, Patrick Ivanova, Elena V. Barbie, David A. Dinulescu, Daniela M. |
| author_sort | Gerton, Thomas J. |
| collection | MIT |
| 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 | 2024-09-23T16:43:40Z |
| format | Article |
| id | mit-1721.1/152071 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T16:43:40Z |
| publishDate | 2023 |
| publisher | Multidisciplinary Digital Publishing Institute |
| record_format | dspace |
| spelling | mit-1721.1/1520712024-01-31T20:27:48Z Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells Gerton, Thomas J. Green, Allen Campisi, Marco Chen, Minyue Gjeci, Iliana Mahadevan, Navin Lee, Catherine A. A. Mishra, Ranjan Vo, Ha V. Haratani, Koji Li, Ze-Hua Hasselblatt, Kathleen T. Testino, Bryanna Connor, Trevor Lian, Christine G. Elias, Kevin M. Lizotte, Patrick Ivanova, Elena V. Barbie, David A. Dinulescu, Daniela M. Whitehead Institute for Biomedical Research 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. 2023-09-08T19:28:34Z 2023-09-08T19:28:34Z 2023-08-16 2023-08-25T12:37:07Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/152071 Cancers 15 (16): 4128 (2023) PUBLISHER_CC http://dx.doi.org/10.3390/cancers15164128 Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Multidisciplinary Digital Publishing Institute Multidisciplinary Digital Publishing Institute |
| spellingShingle | Gerton, Thomas J. Green, Allen Campisi, Marco Chen, Minyue Gjeci, Iliana Mahadevan, Navin Lee, Catherine A. A. Mishra, Ranjan Vo, Ha V. Haratani, Koji Li, Ze-Hua Hasselblatt, Kathleen T. Testino, Bryanna Connor, Trevor Lian, Christine G. Elias, Kevin M. Lizotte, Patrick Ivanova, Elena V. Barbie, David A. Dinulescu, Daniela M. Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells |
| 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 |
| url | https://hdl.handle.net/1721.1/152071 |
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