Defining and targeting tumor-associated macrophages in malignant mesothelioma

Our plain-English summary of Defining and targeting tumor-associated macrophages in malignant mesothelioma, by L. Wu, M. Kohno, J. Murakami, et al (Proceedings of the National Academy of Sciences of the United States of America, 2023).

The study

• Authors: L. Wu, M. Kohno, J. Murakami, A. Zia, J. Allen, H. Yun, M. Chan, C. Baciu, M. Liu, V. Serre-Beinier, M. De Palma, E. Felley-Bosco, J. Yeung, T.J. Pugh, M. de Perrot
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2023;120(9):e2210836120
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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, GPNMB, and MARCO, could 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.

In plain English

This laboratory study examined tumour-associated macrophages (TAM) in mesothelioma using mouse models and human samples. RN5 cells were injected intraperitoneally into C57BL/6 mice and AB12 cells intrapleurally into Balb/c mice. Two macrophage populations were tracked: monocyte-derived small peritoneal/pleural macrophages (SPM) and tissue-resident large peritoneal/pleural macrophages (LPM). SPM rose rapidly after tumour challenge and, by day 10 in the pleural model, made up about 80% of CD206+ TAM. Intrapleural clodronate liposomes depleted both populations by day 3; by day 10 LPM remained absent while SPM were present. Memory mice rejected tumour and survived at least 60 days, whereas clodronate-treated memory mice died after 30 days, though still longer than naive mice. Tumour-bearing Dicer1 myeloid-deficient mice had only 158 genes dysregulated compared with naive mice, against 3,314 in tumour-bearing wild-type mice. Sorted M2-like SPM formed tumours; F4/80hiCD206- cells did not. The SPM gene signature appeared in pleural effusion and tumour from five patients with pleural mesothelioma. Trem2 knockout reduced SPM with a compensatory LPM increase and smaller tumours. The authors concluded that SPM are a critical component in tumour progression.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: mouse mesothelioma experiments (intraperitoneal and intrapleural models, genetic knockouts, macrophage depletion) with transcriptomic and single-cell RNA sequencing, plus single-cell analysis of human mesothelioma samples
• Who was studied: Mice (C57BL/6 given RN5 cells intraperitoneally; Balb/c given AB12 cells intrapleurally; Dicer1 myeloid-deficient, GFP and Trem2 knockout mice) and pleural effusion and tumour biopsy from five patients with pleural mesothelioma
• Exposure: Not an asbestos-exposure study: the manipulations studied were mesothelioma tumour cell challenge, clodronate liposome macrophage depletion, conditional myeloid Dicer1 deletion, and Trem2 gene knockout
• Main results:
  • In the intrapleural mouse model, SPM accumulated by day 3 and represented about 80% of the CD206+ TAM population on day 10; LPM had nearly disappeared by day 14
  • Clodronate liposomes in the pleural cavity depleted both SPM and LPM by day 3, but by day 10 LPM were still absent while SPM and M-MDSC were present
  • Memory mice given intrapleural clodronate liposomes lost tumour rejection: untreated memory mice survived at least 60 days after rechallenge, clodronate-treated memory mice died after 30 days
  • Clodronate-treated memory mice nevertheless survived longer than naive mice, which the authors took as persistent protection from memory T cells
  • Peritoneal lavage from tumour-bearing Dicer1 myeloid-deficient (D−/−) mice showed only 158 genes up- or downregulated relative to naive mice
  • Tumour-bearing wild-type mice, by comparison, had 3,314 genes dysregulated relative to naive mice
  • Sorted M2-like SPM (CD11bloF4/80loCD206+) from tumour-bearing mice produced tumours and mesospheres after injection, whereas the same number of F4/80hiCD206− sorted cells produced no tumours over 3 months
  • Microarray comparison of SPM with LPM in tumour-bearing mice: 421 (1.22%) genes passed filter criteria, 200 (47.51%) upregulated and 221 (52.49%) downregulated
  • Pathway analysis: SPM-specific gene sets showed KRAS and TNF-alpha via NFkB activation; LPM-specific sets showed coagulation, complement and IFN-gamma response
  • In human mesothelioma samples, five upregulated transmembrane genes expressed by SPM-phenotype TAM were proposed as potential therapeutic targets
  • In Trem2 knockout mice given RN5 cells intraperitoneally, SPM fell and LPM rose, with fewer mesospheres and smaller tumours than wild-type mice
• The authors' conclusion: The authors concluded that SPM and LPM phenotypes matter in mesothelioma, that the SPM population is a critical component of tumour progression, and that SPM-like TAM could be a target for immunotherapy, particularly combined with immune checkpoint blockade
• Limitations the authors state:
  • Possible overlap between the SPM and LPM populations, although the authors state the two were distinct enough to yield different gene signatures
  • The interaction between LPM and the memory T cell response was not characterised in detail and needs further study
  • LPM behaved differently in the peritoneal than the pleural cavity, and whether this explains survival differences between pleural and peritoneal mesothelioma remains to be determined

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Macrophage, Mesothelioma, Tumor Microenvironment, Carcinogenesis, Inflammation, Pleural Effusion.

Related studies

• How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations — H. Rehrauer, L. Wu, et al. (2018)
• New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma — N. Joalland, A. Quéméner, et al. (2025)
• Prognostic Significance of B7-H3 Expression and CD163+ Tumor-Associated Macrophage Infiltration in Mesothelioma — T. Koç, R.O. Yüceer, et al. (2026)
• Malignant mesothelioma-associated inflammatory microenvironment promotes tumor progression via GPNMB — C. Belgiovine, E. Digifico, et al. (2025)
• Tumor-associated macrophages in thoracic malignancies — L.A. Lievense, K. Bezemer, et al. (2013)
• Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma — D. Horio, T. Minami, et al. (2020)

Browse more research in Proceedings of the National Academy of Sciences of the United States of America, or return to medical research.