Licun Wu https://orcid.org/0000-0003-4803-9361, Mikihiro Kohno https://orcid.org/0000-0002-8003-7692, Junichi Murakami, Amen Zia https://orcid.org/0000-0002-1239-0857, Jonathan Allen, Hana Yun, Meilin Chan https://orcid.org/0000-0002-5506-2191, Cristina kiss https://orcid.org/0000-0002-3750-5147, Mingyao Liu, Veronique Serre beinier https://orcid.org/0000-0002-6016-1645, Michele Palm https://orcid.org/0000-0001-9128-5459, Emmanuel Felley-Bosco https://orcid.org/0000-0002-3408-0294, Jonathan Yeung, Trevor J. Pughand Marc by Perrot [email protected]Authors Info & Affiliations
Edited by Harvey Cantor, Dana-Farber Cancer Institute, Boston, MA; received June 23, 2022; accepted November 7, 2022
February 23, 2023
120 (9) e2210836120
Significance
Tumor-associated macrophages (TAM) contribute to the immunosuppressive microenvironment of mesothelioma. We focused on the distinct subsets of small and large peritoneal/pleural macrophages (SPM and LPM) to identify their gene signatures. SPM preferentially contribute to M2-like phenotype, while LPM more specifically contributed to the immune response. TREM2, STAB1, LAIR1, GPNMB, and MARCO could potentially provide specific therapeutic targets.
Abstract
Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage populations in mouse peritoneal and pleural cavities, the monocyte-derived, small peritoneal/pleural macrophages (SPM), and the tissue-resident large peritoneal/pleural macrophages (LPM). SPM rapidly increased in tumor microenvironment after tumor challenge and contributed to the vast majority of M2-like TAM. The selective depletion of M2-like TAM by conditional deletion of the Dicer1 gene in myeloid cells (D−/−) promoted tumor rejection. Sorted SPM M2-like TAM initiated tumorigenesis in vivo and in vitro, confirming their capacity to support tumor development. The transcriptomic and single-cell RNA sequencing analysis demonstrated that both SPM and LPM contributed to the tumor microenvironment by promoting the IL-2-STAT5 signaling pathway, inflammation, and epithelial–mesenchymal transition. However, while SPM preferentially activated the KRAS and TNF-α/NFkB signaling pathways, LPM activated the IFN-γ response. The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity. SPM gene signature could be identified in pleural effusion and tumor from patients with untreated mesothelioma. Five genes, TREM2, STAB1, LAIR1, GPNMBand MARCOcould potentially be specific therapeutic targets. Accordingly, Trem2 gene deletion led to reduced SPM M2-like TAM with compensatory increase in LPM and slower tumor growth. Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM.
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Data, Materials, and Software Availability
Acknowledgments
This work was supported by the Mesothelioma Applied Research Foundation, the Princess Margaret Cancer Foundation, and the University Health Network (UHN) Foundation. M.de Perrot is the recipient from the Canadian Mesothelioma Foundation Professorship in Mesothelioma Research.
Author contributions
L.W., E.F.-B., J.Y., and M. de Perrot designed research; L.W., M.K., J.M., H.Y., M.C., V.S.-B., and E.F.-B. performed research; M.L., M. De Palma, and T.J.P. contributed new reagents/analytic tools; L.W., M.K., J.M., A.Z., J.A., H.Y., M.C., C.B., V.S.-B., E.F.-B., and J.Y. analyzed data; J.A. and C.B. discussion about the data presentation; M.L. and T.J.P. participated in study discussion; M.D. participated in study discussion and manuscript editing; J.Y. participation in manuscript discussion; M. de Perrot interpretation of the results; L.W. and M. de Perrot wrote the paper.
Competing interests
The authors have organizational affiliations to disclose. M. De Perrot received personal fees outside of this work from Bayer (speaking fees for work related to pulmonary hypertension), Merck (speaking fees for work related to lung cancer), Janssen (consulting fees for work related to pulmonary hypertension), Roche (consulting fees for work related to lung cancer), BMS (consulting fees for work related to lung cancer), and Astra-Zeneca (Ad board for work related to lung cancer).
Supporting Information
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Information & Authors
Information
Published in
Proceedings of the National Academy of Sciences
Vol. 120 | No. 9
February 28, 2023
Classifications
Copyright
Data, Materials, and Software Availability
Submission history
Received: June 23, 2022
Accepted: November 7, 2022
Published online: February 23, 2023
Published in issue: February 28, 2023
Keywords
- tumor-associated macrophages
- tumor microenvironment
- mesothelioma
- gene signature
- cancer
Acknowledgments
This work was supported by the Mesothelioma Applied Research Foundation, the Princess Margaret Cancer Foundation, and the University Health Network (UHN) Foundation. M.de Perrot is the recipient from the Canadian Mesothelioma Foundation Professorship in Mesothelioma Research.
Author Contributions
L.W., E.F.-B., J.Y., and M. de Perrot designed research; L.W., M.K., J.M., H.Y., M.C., V.S.-B., and E.F.-B. performed research; M.L., M. De Palma, and T.J.P. contributed new reagents/analytic tools; L.W., M.K., J.M., A.Z., J.A., H.Y., M.C., C.B., V.S.-B., E.F.-B., and J.Y. analyzed data; J.A. and C.B. discussion about the data presentation; M.L. and T.J.P. participated in study discussion; M.D. participated in study discussion and manuscript editing; J.Y. participation in manuscript discussion; M. de Perrot interpretation of the results; L.W. and M. de Perrot wrote the paper.
Competing Interests
The authors have organizational affiliations to disclose. M. De Perrot received personal fees outside of this work from Bayer (speaking fees for work related to pulmonary hypertension), Merck (speaking fees for work related to lung cancer), Janssen (consulting fees for work related to pulmonary hypertension), Roche (consulting fees for work related to lung cancer), BMS (consulting fees for work related to lung cancer), and Astra-Zeneca (Ad board for work related to lung cancer).
Notes
This article is a PNAS Direct Submission.
Authors
Affiliations
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Junichi Murakami
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
dYcode Inc., Toronto, ON L6C 2R9, Canada
Jonathan Allen
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Hana Yun
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Mingyao Liu
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Department of Thoracic Surgery, University Hospitals of Geneva, Geneva 1205, Switzerland
Swiss Federal Institute of Technology in Lausanne (Ecole Polytechnique Fédérale de Lausanne), Lausanne 1015, Switzerland
Agora Research Cancer Centre, Lausanne 1005, Switzerland
Laboratory of Molecular Oncology, University Hospital Zurich, University of Zurich, Zürich 8044, Switzerland
Jonathan Yeung
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Trevor J. Pugh
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
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