Frontiers in Immunology (Apr 2022)
Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer
- Rajeev Dhupar,
- Rajeev Dhupar,
- Rajeev Dhupar,
- Katherine E. Jones,
- Amy A. Powers,
- Seth H. Eisenberg,
- Kai Ding,
- Fangyuan Chen,
- Cecile Nasarre,
- Cecile Nasarre,
- Cecile Nasarre,
- Zhanpeng Cen,
- Zhanpeng Cen,
- Zhanpeng Cen,
- Yi-Nan Gong,
- Yi-Nan Gong,
- Amanda C. LaRue,
- Amanda C. LaRue,
- Amanda C. LaRue,
- Elizabeth S. Yeh,
- James D. Luketich,
- Adrian V. Lee,
- Adrian V. Lee,
- Steffi Oesterreich,
- Steffi Oesterreich,
- Michael T. Lotze,
- Michael T. Lotze,
- Michael T. Lotze,
- Michael T. Lotze,
- Robert M. Gemmill,
- Robert M. Gemmill,
- Robert M. Gemmill,
- Adam C. Soloff,
- Adam C. Soloff,
- Adam C. Soloff,
- Adam C. Soloff
Affiliations
- Rajeev Dhupar
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Rajeev Dhupar
- Cancer Immunology and Immunotherapy Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
- Rajeev Dhupar
- Surgical Services Division, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States
- Katherine E. Jones
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Amy A. Powers
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Seth H. Eisenberg
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Kai Ding
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA, United States
- Fangyuan Chen
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA, United States
- Cecile Nasarre
- Division of Hematology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
- Cecile Nasarre
- Division of Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
- Cecile Nasarre
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
- Zhanpeng Cen
- Cancer Immunology and Immunotherapy Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
- Zhanpeng Cen
- School of Medicine, Tsinghua University, Beijing, China
- Zhanpeng Cen
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Yi-Nan Gong
- Cancer Immunology and Immunotherapy Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
- Yi-Nan Gong
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Amanda C. LaRue
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
- Amanda C. LaRue
- 0Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
- Amanda C. LaRue
- 1Research Service, Ralph H. Johnson VA Health Care System, Charleston, SC, United States
- Elizabeth S. Yeh
- 2Department of Pharmacology and Toxicology, Indiana University School of Medicine, Simon Cancer Center, Indianapolis, IN, United States
- James D. Luketich
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Adrian V. Lee
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA, United States
- Adrian V. Lee
- 3Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States
- Steffi Oesterreich
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA, United States
- Steffi Oesterreich
- 3Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States
- Michael T. Lotze
- Cancer Immunology and Immunotherapy Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
- Michael T. Lotze
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Michael T. Lotze
- 4Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Michael T. Lotze
- 5Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Robert M. Gemmill
- Division of Hematology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
- Robert M. Gemmill
- Division of Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
- Robert M. Gemmill
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
- Adam C. Soloff
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Adam C. Soloff
- Cancer Immunology and Immunotherapy Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
- Adam C. Soloff
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
- Adam C. Soloff
- 1Research Service, Ralph H. Johnson VA Health Care System, Charleston, SC, United States
- DOI
- https://doi.org/10.3389/fimmu.2022.830169
- Journal volume & issue
-
Vol. 13
Abstract
Tumor-associated macrophages (TAMs) exert profound influence over breast cancer progression, promoting immunosuppression, angiogenesis, and metastasis. Neuropilin-2 (NRP2), consisting of the NRP2a and NRP2b isoforms, is a co-receptor for heparin-binding growth factors including VEGF-C and Class 3 Semaphorins. Selective upregulation in response to environmental stimuli and independent signaling pathways endow the NRP2 isoforms with unique functionality, with NRP2b promoting increased Akt signaling via receptor tyrosine kinases including VEGFRs, MET, and PDGFR. Although NRP2 has been shown to regulate macrophage/TAM biology, the role of the individual NRP2a/NRP2b isoforms in TAMs has yet to be evaluated. Using transcriptional profiling and spectral flow cytometry, we show that NRP2 isoform expression was significantly higher in TAMs from murine mammary tumors. NRP2a/NRP2b levels in human breast cancer metastasis were dependent upon the anatomic location of the tumor and significantly correlated with TAM infiltration in both primary and metastatic breast cancers. We define distinct phenotypes of NRP2 isoform-expressing TAMs in mouse models of breast cancer and within malignant pleural effusions from breast cancer patients which were exclusive of neuropilin-1 expression. Genetic depletion of either NRP2 isoform in macrophages resulted in a dramatic reduction of LPS-induced IL-10 production, defects in phagosomal processing of apoptotic breast cancer cells, and increase in cancer cell migration following co-culture. By contrast, depletion of NRP2b, but not NRP2a, inhibited production of IL-6. These results suggest that NRP2 isoforms regulate both shared and unique functionality in macrophages and are associated with distinct TAM subsets in breast cancer.
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