STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer
Background Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.Methods PARPi-resistant ovarian cancer mouse models were generated...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-01-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005627.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582693398773760 |
|---|---|
| author | Changli Qian Gordon J Freeman Tao Jiang Ursula Matulonis Ziying Lin Hye-Jung Kim Anniina Färkkilä Hua Yu Xin Cheng Panagiotis A Konstantinopoulos Antons Martincuks Joyce F Liu Qiwei Wang Liya Ding Michael J Kearns Shaozhen Xie Inga-Maria Launonen Thomas M Roberts Jean J Zhao |
| author_facet | Changli Qian Gordon J Freeman Tao Jiang Ursula Matulonis Ziying Lin Hye-Jung Kim Anniina Färkkilä Hua Yu Xin Cheng Panagiotis A Konstantinopoulos Antons Martincuks Joyce F Liu Qiwei Wang Liya Ding Michael J Kearns Shaozhen Xie Inga-Maria Launonen Thomas M Roberts Jean J Zhao |
| author_sort | Changli Qian |
| collection | DOAJ |
| description | Background Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.Methods PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer.Results In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.Conclusions We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer. |
| format | Article |
| id | doaj-art-84e48eba52e74658abc61bd3c1ea75b9 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-84e48eba52e74658abc61bd3c1ea75b92025-01-29T12:00:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005627STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancerChangli Qian0Gordon J Freeman1Tao Jiang2Ursula Matulonis3Ziying Lin4Hye-Jung Kim5Anniina Färkkilä6Hua Yu7Xin Cheng8Panagiotis A Konstantinopoulos9Antons Martincuks10Joyce F Liu11Qiwei Wang12Liya Ding13Michael J Kearns14Shaozhen Xie15Inga-Maria Launonen16Thomas M Roberts17Jean J Zhao18Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA3Dana-Farber Cancer Institute, Boston, MA, USA1 Department of Otolaryngology-Head and Neck Surgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People`s Hospital of Changde City), Changde, Hunan, People`s Republic of China4Dana Farber Cancer Institute, Department of Medicine, Boston, USACancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USACancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA1Faculty of Medicine, Research Program in Systems Oncology, University of Helsinki, Helsinki, FinlandImmuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Neurology, National Center for Neurological Disorders, National Clinical Research Center for Aging and Medicine, Huashan Hospital Fudan University, Shanghai, ChinaMedical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USAMedical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USACancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USACancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USACancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAHFBO Therapeutics, Cambridge, MA, USAObstetrics and Gynecology, University of Helsinki, Helsinki, FinlandCancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USACancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USABackground Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.Methods PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer.Results In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.Conclusions We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.https://jitc.bmj.com/content/11/1/e005627.full |
| spellingShingle | Changli Qian Gordon J Freeman Tao Jiang Ursula Matulonis Ziying Lin Hye-Jung Kim Anniina Färkkilä Hua Yu Xin Cheng Panagiotis A Konstantinopoulos Antons Martincuks Joyce F Liu Qiwei Wang Liya Ding Michael J Kearns Shaozhen Xie Inga-Maria Launonen Thomas M Roberts Jean J Zhao STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer Journal for ImmunoTherapy of Cancer |
| title | STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer |
| title_full | STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer |
| title_fullStr | STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer |
| title_full_unstemmed | STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer |
| title_short | STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer |
| title_sort | sting agonism overcomes stat3 mediated immunosuppression and adaptive resistance to parp inhibition in ovarian cancer |
| url | https://jitc.bmj.com/content/11/1/e005627.full |
| work_keys_str_mv | AT changliqian stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT gordonjfreeman stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT taojiang stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT ursulamatulonis stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT ziyinglin stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT hyejungkim stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT anniinafarkkila stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT huayu stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT xincheng stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT panagiotisakonstantinopoulos stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT antonsmartincuks stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT joycefliu stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT qiweiwang stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT liyading stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT michaeljkearns stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT shaozhenxie stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT ingamarialaunonen stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT thomasmroberts stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer AT jeanjzhao stingagonismovercomesstat3mediatedimmunosuppressionandadaptiveresistancetoparpinhibitioninovariancancer |