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.
Original language | English (US) |
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Article number | e153242 |
Journal | JCI Insight |
Volume | 7 |
Issue number | 22 |
DOIs | |
State | Published - Nov 22 2022 |
Bibliographical note
Funding Information:This work was supported by the NIH (R01CA181385, U54CA210190, University of Minnesota Physical Sciences in Oncology Center, and U54CA268069, CCBIR Center for Multiparametric Imaging of Tumor Immune Microenvironments, to PPP; and R01CA245550 to PPP) and by American Cancer Society Research Scholar (RSG-14-171-01-CSM) and Mission Boost (MBGI-22-009-01-MBG) Grants. This work was also supported by the Randy Shaver Research and Community Fund (to PPP). AS is supported by the National Cancer Institute (R50CA211249) and a Masonic Cancer Center Comprehensive Cancer Center Support Grant (R50CA077598). RAB is supported by the NIH (R01CA243577 and U54CA210181 Project 2), and HH is supported by an NIH award (K99CA252009). We also thank ChemoCentryx for providing CCR2i (CCX598) and members of the Provenzano laboratory for insightful comments and help regarding this work. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies.
Publisher Copyright:
© 2022, Dixit et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.