Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment
Background Pancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a dri...
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| Language: | English |
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BMJ Publishing Group
2024-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/12/e009523.full |
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| author | David Liberg Petter Skoog Caitríona Grönberg Nils Hansen Pablo Peña-Martínez Katrin Reinbach Finja C Hansen Susanne Larsson Faria Kawther Abdilleh Susanne Magnusson Karin von Wachenfeldt Camilla Rydberg Millrud Marcus Järås |
| author_facet | David Liberg Petter Skoog Caitríona Grönberg Nils Hansen Pablo Peña-Martínez Katrin Reinbach Finja C Hansen Susanne Larsson Faria Kawther Abdilleh Susanne Magnusson Karin von Wachenfeldt Camilla Rydberg Millrud Marcus Järås |
| author_sort | David Liberg |
| collection | DOAJ |
| description | Background Pancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a driver in this process. Mechanistically, both IL-1α and IL-1β bind to the IL-1 receptor type 1, forming a complex with IL-1-receptor accessory protein (IL1RAP), which triggers downstream signaling pathways. The IL1RAP blocking antibody nadunolimab is currently in clinical development, but the precise consequences of inhibiting IL-1 signaling in PDAC remains elusive.Methods To evaluate the biological relevance of blocking IL1RAP using nadunolimab in a PDAC animal model, human PDAC cells and cancer-associated fibroblasts (CAFs) were co-transplanted into mice. To study the underlying mechanisms of IL1RAP blockade ex vivo, co-cultured PDAC cells and CAFs were treated with nadunolimab prior to RNA sequencing. Migration assays were performed to assess how nadunolimab affects interactions between CAFs and myeloid immune cells. Finally, to establish a clinical correlation between IL1RAP expression and nadunolimab treatment effects, we analyzed tumor biopsies from a clinical phase I/II study in which nadunolimab was administered to patients.Results In the xenograft mouse model, nadunolimab exhibited antitumor effects only when human CAFs were co-transplanted with PDAC cells. IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes. The secretion of this chemokine and the migration of myeloid cells were inhibited by nadunolimab. Media conditioned by IL-1-stimulated CAFs sustained a neutrophil population with a tissue invasion phenotype, an effect that was reversed by nadunolimab. In a cohort of metastatic late-stage PDAC patients receiving nadunolimab as monotherapy, high IL1RAP expression in tumors was associated with extended progression-free survival.Conclusions Our study demonstrates that targeting IL1RAP on CAFs inhibits IL-1-induced chemokine secretion and recruitment of neutrophils and monocytes, thereby counteracting the immunosuppressive microenvironment in PDAC. These findings highlight the therapeutic potential of targeting IL1RAP in PDAC. |
| format | Article |
| id | doaj-art-112dc3e1ca4c43338ff8cc2c448e9390 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-112dc3e1ca4c43338ff8cc2c448e93902025-08-20T01:58:42ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-12-01121210.1136/jitc-2024-009523Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitmentDavid Liberg0Petter Skoog1Caitríona Grönberg2Nils Hansen3Pablo Peña-Martínez4Katrin Reinbach5Finja C Hansen6Susanne Larsson Faria7Kawther Abdilleh8Susanne Magnusson9Karin von Wachenfeldt10Camilla Rydberg Millrud11Marcus Järås12Cantargia AB, Lund, SwedenCantargia AB, Lund, Sweden3Cantargia AB, Lund, Sweden1 Lund Stem Cell Center, Lund University, Lund, Sweden1 Lund Stem Cell Center, Lund University, Lund, Sweden1 Lund Stem Cell Center, Lund University, Lund, Sweden1 Lund Stem Cell Center, Lund University, Lund, Sweden3 Truly Labs AB, Lund, Sweden4 Pancreatic Cancer Action Network, Manhattan Beach, California, USA2 Cantargia AB, Lund, Sweden3 Truly Labs AB, Lund, Sweden2 Cantargia AB, Lund, Sweden1 Lund Stem Cell Center, Lund University, Lund, SwedenBackground Pancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a driver in this process. Mechanistically, both IL-1α and IL-1β bind to the IL-1 receptor type 1, forming a complex with IL-1-receptor accessory protein (IL1RAP), which triggers downstream signaling pathways. The IL1RAP blocking antibody nadunolimab is currently in clinical development, but the precise consequences of inhibiting IL-1 signaling in PDAC remains elusive.Methods To evaluate the biological relevance of blocking IL1RAP using nadunolimab in a PDAC animal model, human PDAC cells and cancer-associated fibroblasts (CAFs) were co-transplanted into mice. To study the underlying mechanisms of IL1RAP blockade ex vivo, co-cultured PDAC cells and CAFs were treated with nadunolimab prior to RNA sequencing. Migration assays were performed to assess how nadunolimab affects interactions between CAFs and myeloid immune cells. Finally, to establish a clinical correlation between IL1RAP expression and nadunolimab treatment effects, we analyzed tumor biopsies from a clinical phase I/II study in which nadunolimab was administered to patients.Results In the xenograft mouse model, nadunolimab exhibited antitumor effects only when human CAFs were co-transplanted with PDAC cells. IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes. The secretion of this chemokine and the migration of myeloid cells were inhibited by nadunolimab. Media conditioned by IL-1-stimulated CAFs sustained a neutrophil population with a tissue invasion phenotype, an effect that was reversed by nadunolimab. In a cohort of metastatic late-stage PDAC patients receiving nadunolimab as monotherapy, high IL1RAP expression in tumors was associated with extended progression-free survival.Conclusions Our study demonstrates that targeting IL1RAP on CAFs inhibits IL-1-induced chemokine secretion and recruitment of neutrophils and monocytes, thereby counteracting the immunosuppressive microenvironment in PDAC. These findings highlight the therapeutic potential of targeting IL1RAP in PDAC.https://jitc.bmj.com/content/12/12/e009523.full |
| spellingShingle | David Liberg Petter Skoog Caitríona Grönberg Nils Hansen Pablo Peña-Martínez Katrin Reinbach Finja C Hansen Susanne Larsson Faria Kawther Abdilleh Susanne Magnusson Karin von Wachenfeldt Camilla Rydberg Millrud Marcus Järås Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment Journal for ImmunoTherapy of Cancer |
| title | Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment |
| title_full | Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment |
| title_fullStr | Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment |
| title_full_unstemmed | Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment |
| title_short | Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment |
| title_sort | blocking il1rap on cancer associated fibroblasts in pancreatic ductal adenocarcinoma suppresses il 1 induced neutrophil recruitment |
| url | https://jitc.bmj.com/content/12/12/e009523.full |
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