Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models
Background Recent preclinical and clinical data suggest that leukemia inhibitory factor (LIF) is a potential target for various tumor types including pancreatic ductal adenocarcinoma as LIF is involved in multiple protumor processes including cancer stem cell maintenance, epithelial–mesenchymal tran...
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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/e010820.full |
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| author | Jian Ye Brian A Belt Shuyang S Qin Rachel Jewell Laura M Calvi Bradley N Mills Tara G Vrooman Carl J Johnston Scott A Gerber Angela L Hughson Gary Hannon Maggie L Lesch Jim Eyles Nadia Luheshi Noah A Salama Sidney Lesser Sarah L Eckl Lauren Benoodt Edith Lord David Linehan |
| author_facet | Jian Ye Brian A Belt Shuyang S Qin Rachel Jewell Laura M Calvi Bradley N Mills Tara G Vrooman Carl J Johnston Scott A Gerber Angela L Hughson Gary Hannon Maggie L Lesch Jim Eyles Nadia Luheshi Noah A Salama Sidney Lesser Sarah L Eckl Lauren Benoodt Edith Lord David Linehan |
| author_sort | Jian Ye |
| collection | DOAJ |
| description | Background Recent preclinical and clinical data suggest that leukemia inhibitory factor (LIF) is a potential target for various tumor types including pancreatic ductal adenocarcinoma as LIF is involved in multiple protumor processes including cancer stem cell maintenance, epithelial–mesenchymal transition (EMT), immunosuppression, and chemo/radioresistance. Anti-LIF antibody therapy has demonstrated safety and tolerability but limited efficacy in phase 1 clinical trial in advanced solid tumors. This prompted us to explore combination therapies, suggesting that LIF blockade, when combined with standard-of-care chemotherapy, radiotherapy, and/or immunotherapy, could present a promising therapeutic strategy.Methods We evaluated the impact of combining systemic inhibition of LIF/programmed death-ligand 1 (PD-L1) with localized stereotactic body radiotherapy (SBRT) on tumor progression across multiple murine orthotopic pancreatic tumor models and examined systemic antitumor immunity using a hepatic rechallenge model. The antitumor immune response was characterized throughflow cytometry and Luminex assays. To identify differentially expressed genes and signaling pathways following treatment, we performed bulk RNA sequencing on pancreatic tumors. Additionally, single-cell RNA sequencing was conducted to further examine changes in tumor-infiltrating immune cells and their signaling pathways.Results We showed that simultaneous inhibition of LIF and PD-L1 significantly amplified the antitumor efficacy of SBRT, resulting in extended survival. The triple therapy (SBRT+anti-LIF+anti-PD-L1) generated an immunostimulatory tumor microenvironment, characterized by a proinflammatory shift in the cytokine/chemokine profile, increased infiltration of effector CD8+ T cells, and upregulated activation or maturation signals in tumor-infiltrating CD8+ T cells and macrophages. The beneficial effects of triple therapy were mostly abrogated by depletion of CD8+ T cells. In addition, triple therapy downregulated pathways related to tumor stemness, proliferation, and metabolism, and reduced EMT. Importantly, the combination of local SBRT treatment with systemic LIF and PD-L1 blockade resulted in long-term systemic antitumor memory. |
| format | Article |
| id | doaj-art-0e7045baf95645e4a6b7ed3fd00b84da |
| 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-0e7045baf95645e4a6b7ed3fd00b84da2025-08-20T01:49:01ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-05-0113510.1136/jitc-2024-010820Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC modelsJian Ye0Brian A Belt1Shuyang S Qin2Rachel Jewell3Laura M Calvi4Bradley N Mills5Tara G Vrooman6Carl J Johnston7Scott A Gerber8Angela L Hughson9Gary Hannon10Maggie L Lesch11Jim Eyles12Nadia Luheshi13Noah A Salama14Sidney Lesser15Sarah L Eckl16Lauren Benoodt17Edith Lord18David Linehan192 Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA5 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA5 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA5 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA9 Oncology R&D, Research and Early Development, AstraZeneca R&D, Cambridge, Cambridgeshire, UK8 The Discovery Center, Cambridge Biomedical Campus, Cambridge, UK3 Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA4 Genomic Research Center, University of Rochester Medical Center, Rochester, New York, USA2 Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USABackground Recent preclinical and clinical data suggest that leukemia inhibitory factor (LIF) is a potential target for various tumor types including pancreatic ductal adenocarcinoma as LIF is involved in multiple protumor processes including cancer stem cell maintenance, epithelial–mesenchymal transition (EMT), immunosuppression, and chemo/radioresistance. Anti-LIF antibody therapy has demonstrated safety and tolerability but limited efficacy in phase 1 clinical trial in advanced solid tumors. This prompted us to explore combination therapies, suggesting that LIF blockade, when combined with standard-of-care chemotherapy, radiotherapy, and/or immunotherapy, could present a promising therapeutic strategy.Methods We evaluated the impact of combining systemic inhibition of LIF/programmed death-ligand 1 (PD-L1) with localized stereotactic body radiotherapy (SBRT) on tumor progression across multiple murine orthotopic pancreatic tumor models and examined systemic antitumor immunity using a hepatic rechallenge model. The antitumor immune response was characterized throughflow cytometry and Luminex assays. To identify differentially expressed genes and signaling pathways following treatment, we performed bulk RNA sequencing on pancreatic tumors. Additionally, single-cell RNA sequencing was conducted to further examine changes in tumor-infiltrating immune cells and their signaling pathways.Results We showed that simultaneous inhibition of LIF and PD-L1 significantly amplified the antitumor efficacy of SBRT, resulting in extended survival. The triple therapy (SBRT+anti-LIF+anti-PD-L1) generated an immunostimulatory tumor microenvironment, characterized by a proinflammatory shift in the cytokine/chemokine profile, increased infiltration of effector CD8+ T cells, and upregulated activation or maturation signals in tumor-infiltrating CD8+ T cells and macrophages. The beneficial effects of triple therapy were mostly abrogated by depletion of CD8+ T cells. In addition, triple therapy downregulated pathways related to tumor stemness, proliferation, and metabolism, and reduced EMT. Importantly, the combination of local SBRT treatment with systemic LIF and PD-L1 blockade resulted in long-term systemic antitumor memory.https://jitc.bmj.com/content/13/5/e010820.full |
| spellingShingle | Jian Ye Brian A Belt Shuyang S Qin Rachel Jewell Laura M Calvi Bradley N Mills Tara G Vrooman Carl J Johnston Scott A Gerber Angela L Hughson Gary Hannon Maggie L Lesch Jim Eyles Nadia Luheshi Noah A Salama Sidney Lesser Sarah L Eckl Lauren Benoodt Edith Lord David Linehan Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models Journal for ImmunoTherapy of Cancer |
| title | Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models |
| title_full | Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models |
| title_fullStr | Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models |
| title_full_unstemmed | Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models |
| title_short | Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models |
| title_sort | blocking lif and pd l1 enhances the antitumor efficacy of sbrt in murine pdac models |
| url | https://jitc.bmj.com/content/13/5/e010820.full |
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