IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity
Background Immune checkpoint blockers (ICBs) have revolutionized cancer therapy, yet they remain largely ineffective in treating pancreatic ductal adenocarcinoma (PDAC). Moreover, ICBs can cause severe immune-related adverse events (irAEs), including fatal cardiac toxicity. Finally, obesity is a ris...
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BMJ Publishing Group
2025-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/5/e011404.full |
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| author | Dan G Duda Dai Fukumura Rakesh K Jain Peigen Huang Patrik Andersson Mikael J Pittet Heena Kumra William W Ho Nilesh P Talele Igor L Gomes-Santos Marie Siwicki |
| author_facet | Dan G Duda Dai Fukumura Rakesh K Jain Peigen Huang Patrik Andersson Mikael J Pittet Heena Kumra William W Ho Nilesh P Talele Igor L Gomes-Santos Marie Siwicki |
| author_sort | Dan G Duda |
| collection | DOAJ |
| description | Background Immune checkpoint blockers (ICBs) have revolutionized cancer therapy, yet they remain largely ineffective in treating pancreatic ductal adenocarcinoma (PDAC). Moreover, ICBs can cause severe immune-related adverse events (irAEs), including fatal cardiac toxicity. Finally, obesity is a risk factor in PDAC that may differentially modulate ICB efficacy in a malignancy-dependent manner.Methods We investigated the mechanisms underlying irAEs induced by dual ICB therapy and sought to identify strategies to mitigate them while improving ICB efficacy in the obese setting. To this end, we used a clinically relevant mouse model that integrated key features of human PDAC: (1) high-fat diet-induced obesity, (2) an orthotopic PDAC, and (3) a therapeutic regimen combining chemotherapy (FOLFIRINOX) with ICBs (α-programmed cell death protein-1 + α-cytotoxic T-lymphocyte associated protein-4 antibodies).Results Obese mice developed cardiac irAEs and had elevated serum interleukin (IL)-1β levels after chemoimmunotherapy. IL-1β blockade not only prevented myocarditis and reduced cardiac fibrosis but also enhanced the antitumor efficacy of the combination of chemotherapy plus dual ICB therapy and significantly improved the overall survival of PDAC-bearing obese mice.Conclusions Our findings provide the rationale and compelling data to test a Food and Drug Administration-approved anti-IL-1β antibody in combination with chemotherapy and dual ICB therapy in patients with pancreatic cancer with obesity. |
| format | Article |
| id | doaj-art-ac7b3c9b7b7b4764b0d46bcc47ff8242 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ac7b3c9b7b7b4764b0d46bcc47ff82422025-08-20T01:52:23ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-05-0113510.1136/jitc-2024-011404IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesityDan G Duda0Dai Fukumura1Rakesh K Jain2Peigen Huang3Patrik Andersson4Mikael J Pittet5Heena Kumra6William W Ho7Nilesh P Talele8Igor L Gomes-Santos9Marie Siwicki101 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA1 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA1 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA1 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA1 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA6 AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland1 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA1 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA1 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA1 Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA3 Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, USABackground Immune checkpoint blockers (ICBs) have revolutionized cancer therapy, yet they remain largely ineffective in treating pancreatic ductal adenocarcinoma (PDAC). Moreover, ICBs can cause severe immune-related adverse events (irAEs), including fatal cardiac toxicity. Finally, obesity is a risk factor in PDAC that may differentially modulate ICB efficacy in a malignancy-dependent manner.Methods We investigated the mechanisms underlying irAEs induced by dual ICB therapy and sought to identify strategies to mitigate them while improving ICB efficacy in the obese setting. To this end, we used a clinically relevant mouse model that integrated key features of human PDAC: (1) high-fat diet-induced obesity, (2) an orthotopic PDAC, and (3) a therapeutic regimen combining chemotherapy (FOLFIRINOX) with ICBs (α-programmed cell death protein-1 + α-cytotoxic T-lymphocyte associated protein-4 antibodies).Results Obese mice developed cardiac irAEs and had elevated serum interleukin (IL)-1β levels after chemoimmunotherapy. IL-1β blockade not only prevented myocarditis and reduced cardiac fibrosis but also enhanced the antitumor efficacy of the combination of chemotherapy plus dual ICB therapy and significantly improved the overall survival of PDAC-bearing obese mice.Conclusions Our findings provide the rationale and compelling data to test a Food and Drug Administration-approved anti-IL-1β antibody in combination with chemotherapy and dual ICB therapy in patients with pancreatic cancer with obesity.https://jitc.bmj.com/content/13/5/e011404.full |
| spellingShingle | Dan G Duda Dai Fukumura Rakesh K Jain Peigen Huang Patrik Andersson Mikael J Pittet Heena Kumra William W Ho Nilesh P Talele Igor L Gomes-Santos Marie Siwicki IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity Journal for ImmunoTherapy of Cancer |
| title | IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity |
| title_full | IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity |
| title_fullStr | IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity |
| title_full_unstemmed | IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity |
| title_short | IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity |
| title_sort | il 1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity |
| url | https://jitc.bmj.com/content/13/5/e011404.full |
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