Targeting TNF-α producing macrophages activate antitumor immunity in pancreatic cancer through IL33 signaling

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

doi:10.1172/jci.insight.153242

Targeting TNF-α producing macrophages activate antitumor immunity in pancreatic cancer through IL33 signaling

Ajay Dixit,¹ Aaron L. Sarver,² Jon Zettervall,¹ Huocong Huang,³ Kexin Zheng,¹ Rolf A. Brekken,³ and Paolo Provenzano¹

Published October 18, 2022 - More info

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Abstract

Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely due 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. Here, 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 IL33 in carcinoma cells. Deletion of Ccr2 in genetically engineered mice decreases monocyte recruitment resulting in profoundly decreased TNF-α and increased IL33 expression, decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) renders PDA susceptible to checkpoint blockade resulting in reduced metastatic burden and increased survival. Our data indicate that this shift in anti-tumor 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.

Targeting TNF-α producing macrophages activate antitumor immunity in pancreatic cancer through IL33 signaling

Ajay Dixit,¹ Aaron L. Sarver,² Jon Zettervall,¹ Huocong Huang,³ Kexin Zheng,¹ Rolf A. Brekken,³ and Paolo Provenzano¹

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Targeting TNF-α producing macrophages activate antitumor immunity in pancreatic cancer through IL33 signaling

Ajay Dixit,1 Aaron L. Sarver,2 Jon Zettervall,1 Huocong Huang,3 Kexin Zheng,1 Rolf A. Brekken,3 and Paolo Provenzano1

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Ajay Dixit,¹ Aaron L. Sarver,² Jon Zettervall,¹ Huocong Huang,³ Kexin Zheng,¹ Rolf A. Brekken,³ and Paolo Provenzano¹