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Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling
Ajay Dixit, … , Rolf A. Brekken, Paolo P. Provenzano
Ajay Dixit, … , Rolf A. Brekken, Paolo P. Provenzano
Published October 18, 2022
Citation Information: JCI Insight. 2022;7(22):e153242. https://doi.org/10.1172/jci.insight.153242.
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Research Article Oncology

Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling

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Abstract

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.

Authors

Ajay Dixit, Aaron Sarver, Jon Zettervall, Huocong Huang, Kexin Zheng, Rolf A. Brekken, Paolo P. Provenzano

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Figure 9

Increases in IL-33 induce increases in CD8+ cytotoxic T cell levels.

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Increases in IL-33 induce increases in CD8+ cytotoxic T cell levels.
(A ...
(A and B) IF staining shows significantly decreased TNF-α levels in KPC-CCR2–/– and Gem+ICB+CCR2i treatment groups compared with KPC and Gem groups. P value by Mann-Whitney test; n = 4–5 animals. (C and D) Treatment of KPC cells with recombinant TNF-α causes a decrease in IL-33 at the gene and protein levels. P value by Kruskal-Wallis and Dunn’s multiple-comparison tests; n = 3. (E) Strong correlations between IL-33 and markers of CD103+ DC levels and functionality (TCGA data set analysis). (F) IF staining shows a significant increase in CD103+ DCs in Gem+ICB+CCR2i treatment group. P value by Mann-Whitney test; n = 4–5 animals. (G) Analysis of tumor growth curves for control and rIL-33 mice shows that IL-33 decreases the size of subcutaneous PDA tumors and overall tumor volume at the endpoint (n = 3 per group). (H) IF staining and quantification demonstrate that IL-33 increases CD8+ T cell numbers in PDA tumors. P value by Mann-Whitney test; n = 3 animals per group. Scale bars: 10 μm.

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