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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 3

Both iCAFs and myCAFs secrete high levels of CCL2 in PDA tumor microenvironments.

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Both iCAFs and myCAFs secrete high levels of CCL2 in PDA tumor microenvi...
(A) Human TCGA data set analysis shows a strong correlation between expression levels of CCL2 and CD14. (B) CCL2 is overexpressed in human PDA. IHC analysis demonstrates high expression of CCL2 in both human primary PDA tumors and metastatic lesion (lung). (C) CCL2 is also overexpressed in the genetically engineered KPC model of PDA at all stages. IHC shows high expression in PanINs, primary tumor, and metastatic lesions (liver). (D) CCL2 is colocalized with carcinoma cells and both α-SMAlo and α-SMAhi cells in the stroma of both human and murine PDA. Scale bars: 50 μm (B–D). (E) Metastatic cancer cells secrete higher levels of CCL2 than carcinoma cells derived from primary tumors (CCL2 levels were measured in culture supernatant by ELISA for paired primary and metastatic cell lines derived from KPC mice). (F) CAFs secrete higher CCL2 than carcinoma cells. CCL2 levels in culture supernatant of CAFs (grown on 2D culture plates with serum, i.e., myCAFs) and carcinoma cells were measured by ELISA (n = 5–7 KPC cell lines; P value was derived by Mann-Whitney test). (G and H) CAFs are the major CCL2 contributors in PDA. Violin plots of Ccl2 transcripts for individual cell populations in KPC PDA show that iCAFs and myCAFs both express higher levels of Ccl2 compared with other tumor cell populations. The expression of Ccl2 in both myCAFs and iCAFs was validated experimentally by quantitative PCR (n = 5–7 KPC cell lines; P value was derived by Mann-Whitney U test). (I) Strong correlations between CCL2 and both iCAF marker genes (CXCL1, LIF) and myCAF marker genes (ACTA, CTGF) in human TCGA data sets demonstrating that CCL2 is highly expressed by both iCAFs and myCAFs.

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