Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression
The tumor microenvironment (TME) in ovarian cancer (OC) is characterized by immune suppression, due to an abundance of suppressive immune cells populations. To effectively enhance the activity of immune checkpoint inhibition (ICI), there is a need to identify agents that target these immunosuppressi...
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2198185 |
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| author | Paul G. Pavicic Patricia A. Rayman Shadi Swaidani Amit Rupani Vladimir Makarov Charles S. Tannenbaum Robert P. Edwards Anda M. Vlad C. Marcela Diaz-Montero Haider Mahdi |
| author_facet | Paul G. Pavicic Patricia A. Rayman Shadi Swaidani Amit Rupani Vladimir Makarov Charles S. Tannenbaum Robert P. Edwards Anda M. Vlad C. Marcela Diaz-Montero Haider Mahdi |
| author_sort | Paul G. Pavicic |
| collection | DOAJ |
| description | The tumor microenvironment (TME) in ovarian cancer (OC) is characterized by immune suppression, due to an abundance of suppressive immune cells populations. To effectively enhance the activity of immune checkpoint inhibition (ICI), there is a need to identify agents that target these immunosuppressive networks while promoting the recruitment of effector T cells into the TME. To this end, we sought to investigate the effect of the immunomodulatory cytokine IL12 alone or in combination with dual-ICI (anti-PD1 + anti-CTLA4) on anti-tumor activity and survival, using the immunocompetent ID8-VEGF murine OC model. Detailed immunophenotyping of peripheral blood, ascites, and tumors revealed that durable treatment responses were associated with reversal of myeloid cell-induced immune suppression, which resulted in enhanced anti-tumor activity by T cells. Single cell transcriptomic analysis further demonstrated striking differences in the phenotype of myeloid cells from mice treated with IL12 in combination with dual-ICI. We also identified marked differences in treated mice that were in remission compared to those whose tumors progressed, further confirming a pivotal role for the modulation of myeloid cell function to allow for response to immunotherapy. These findings provide the scientific basis for the combination of IL12 and ICI to improve clinical response in OC. |
| format | Article |
| id | doaj-art-5b7a38e7bf7d49fea8f8e68b5ef7c651 |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-5b7a38e7bf7d49fea8f8e68b5ef7c6512025-08-20T02:50:44ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2023.2198185Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppressionPaul G. Pavicic0Patricia A. Rayman1Shadi Swaidani2Amit Rupani3Vladimir Makarov4Charles S. Tannenbaum5Robert P. Edwards6Anda M. Vlad7C. Marcela Diaz-Montero8Haider Mahdi9Center for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USACenter for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USACenter for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USACenter for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USACenter for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USADepartment of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USADepartment of Obstetrics, Gynecology and Reproductive Sciences and Magee Women’s Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Obstetrics, Gynecology and Reproductive Sciences and Magee Women’s Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USACenter for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USADepartment of Obstetrics, Gynecology and Reproductive Sciences and Magee Women’s Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAThe tumor microenvironment (TME) in ovarian cancer (OC) is characterized by immune suppression, due to an abundance of suppressive immune cells populations. To effectively enhance the activity of immune checkpoint inhibition (ICI), there is a need to identify agents that target these immunosuppressive networks while promoting the recruitment of effector T cells into the TME. To this end, we sought to investigate the effect of the immunomodulatory cytokine IL12 alone or in combination with dual-ICI (anti-PD1 + anti-CTLA4) on anti-tumor activity and survival, using the immunocompetent ID8-VEGF murine OC model. Detailed immunophenotyping of peripheral blood, ascites, and tumors revealed that durable treatment responses were associated with reversal of myeloid cell-induced immune suppression, which resulted in enhanced anti-tumor activity by T cells. Single cell transcriptomic analysis further demonstrated striking differences in the phenotype of myeloid cells from mice treated with IL12 in combination with dual-ICI. We also identified marked differences in treated mice that were in remission compared to those whose tumors progressed, further confirming a pivotal role for the modulation of myeloid cell function to allow for response to immunotherapy. These findings provide the scientific basis for the combination of IL12 and ICI to improve clinical response in OC.https://www.tandfonline.com/doi/10.1080/2162402X.2023.2198185Ovarian cancerimmunotherapyInterleukin 12checkpoint blockademyeloid cells |
| spellingShingle | Paul G. Pavicic Patricia A. Rayman Shadi Swaidani Amit Rupani Vladimir Makarov Charles S. Tannenbaum Robert P. Edwards Anda M. Vlad C. Marcela Diaz-Montero Haider Mahdi Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression OncoImmunology Ovarian cancer immunotherapy Interleukin 12 checkpoint blockade myeloid cells |
| title | Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression |
| title_full | Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression |
| title_fullStr | Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression |
| title_full_unstemmed | Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression |
| title_short | Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression |
| title_sort | immunotherapy with il12 and pd1 ctla4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell induced immunosuppression |
| topic | Ovarian cancer immunotherapy Interleukin 12 checkpoint blockade myeloid cells |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2198185 |
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