Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling
Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely owing to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance, and recent studie...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.153242 |
| _version_ | 1797634395187707904 |
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| author | Ajay Dixit Aaron Sarver Jon Zettervall Huocong Huang Kexin Zheng Rolf A. Brekken Paolo P. Provenzano |
| author_facet | Ajay Dixit Aaron Sarver Jon Zettervall Huocong Huang Kexin Zheng Rolf A. Brekken Paolo P. Provenzano |
| author_sort | Ajay Dixit |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely owing to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance, and recent studies targeting macrophages in combination with checkpoint blockade have demonstrated promising preclinical results. Yet our understanding of tumor-associated macrophage (TAM) function, complexity, and diversity in PDA remains limited. Our analysis reveals significant macrophage heterogeneity, with bone marrow–derived monocytes serving as the primary source for immunosuppressive TAMs. These cells also serve as a primary source of TNF-α, which suppresses expression of the alarmin IL-33 in carcinoma cells. Deletion of Ccr2 in genetically engineered mice decreased monocyte recruitment, resulting in profoundly decreased TNF-α and increased IL-33 expression, decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) rendered PDA susceptible to checkpoint blockade, resulting in reduced metastatic burden and increased survival. Our data indicate that this shift in antitumor immunity is influenced by increased levels of IL-33, which increases dendritic cell and cytotoxic T cell activity. These data demonstrate that interventions to disrupt infiltration of immunosuppressive macrophages, or their signaling, have the potential to overcome barriers to effective immunotherapeutics for PDA. |
| first_indexed | 2024-03-11T12:07:05Z |
| format | Article |
| id | doaj.art-dc7eef9351654893b8a124a012fbb9ef |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:05Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-dc7eef9351654893b8a124a012fbb9ef2023-11-07T16:24:51ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-11-01722Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signalingAjay DixitAaron SarverJon ZettervallHuocong HuangKexin ZhengRolf A. BrekkenPaolo P. ProvenzanoPancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely owing to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance, and recent studies targeting macrophages in combination with checkpoint blockade have demonstrated promising preclinical results. Yet our understanding of tumor-associated macrophage (TAM) function, complexity, and diversity in PDA remains limited. Our analysis reveals significant macrophage heterogeneity, with bone marrow–derived monocytes serving as the primary source for immunosuppressive TAMs. These cells also serve as a primary source of TNF-α, which suppresses expression of the alarmin IL-33 in carcinoma cells. Deletion of Ccr2 in genetically engineered mice decreased monocyte recruitment, resulting in profoundly decreased TNF-α and increased IL-33 expression, decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) rendered PDA susceptible to checkpoint blockade, resulting in reduced metastatic burden and increased survival. Our data indicate that this shift in antitumor immunity is influenced by increased levels of IL-33, which increases dendritic cell and cytotoxic T cell activity. These data demonstrate that interventions to disrupt infiltration of immunosuppressive macrophages, or their signaling, have the potential to overcome barriers to effective immunotherapeutics for PDA.https://doi.org/10.1172/jci.insight.153242Oncology |
| spellingShingle | Ajay Dixit Aaron Sarver Jon Zettervall Huocong Huang Kexin Zheng Rolf A. Brekken Paolo P. Provenzano Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling JCI Insight Oncology |
| title | Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling |
| title_full | Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling |
| title_fullStr | Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling |
| title_full_unstemmed | Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling |
| title_short | Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling |
| title_sort | targeting tnf α producing macrophages activates antitumor immunity in pancreatic cancer via il 33 signaling |
| topic | Oncology |
| url | https://doi.org/10.1172/jci.insight.153242 |
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