Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma

Our plain-English summary of Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma, by T. Blondy, S.M. d'Almeida, T. Briolay, et al (Journal for Immunotherapy of Cancer, 2020).

The study

• Authors: T. Blondy, S.M. d'Almeida, T. Briolay, J. Tabiasco, C. Meiller, A.L. Chéné, L. Cellerin, S. Deshayes, Y. Delneste, J.F. Fonteneau, N. Boisgerault, J. Bennouna, M. Grégoire, D. Jean, C. Blanquart
• Journal: Journal for Immunotherapy of Cancer
• Published: 2020;8(1)
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The tumor microenvironment content, particularly the presence of macrophages, was described as crucial for the development of the disease. This work aimed at studying the involvement of the M-CSF (CSF-1)/IL-34/CSF-1R pathway in the formation of macrophages in MPM, using samples from patients.

Methods: Pleural effusions (PEs), frozen tumors, primary MPM cells and MPM cell lines used in this study belong to biocollections associated with clinical databases. Cytokine expressions were studied using real-time PCR and ELISA. The Cancer Genome Atlas database was used to confirm our results on an independent cohort. An original three-dimensional (3D) coculture model including MPM cells, monocytes from healthy donors and a tumor antigen-specific cytotoxic CD8 T cell clone was used.

Results: We observed that high interleukin (IL)-34 levels in PE were significantly associated with a shorter survival of patients. In tumors, expression of CSF1 was correlated with 'M2-like macrophages' markers, whereas this was not the case with IL34 expression, suggesting two distinct modes of action of these cytokines. Expression of IL34 was higher in MPM cells compared with primary mesothelial cells. Particularly, high expression of IL34 was observed in MPM cells with an alteration of CDKN2A. Finally, using 3D coculture model, we demonstrated the direct involvement of MPM cells in the formation of immunosuppressive macrophages, through activation of the colony stimulating factor-1 receptor (CSF1-R) pathway, causing the inhibition of cytotoxicity of tumor antigen-specific CD8+ T cells.

Conclusions: The M-CSF/IL-34/CSF-1R pathway seems strongly implicated in MPM and could constitute a therapeutic target to act on immunosuppression and to support immunotherapeutic strategies.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This laboratory study from France examined two signalling proteins, M-CSF and IL-34, in malignant pleural mesothelioma. Both act on a receptor called CSF-1R, which helps turn white blood cells called monocytes into macrophages. Asbestos exposure was not studied as a factor, although 68.7% of the mesothelioma patients whose pleural fluid was tested had confirmed exposure. The authors tested pleural fluid from 96 mesothelioma patients, 105 patients with other cancers and 26 patients with benign effusions. They also tested tumour tissue and cultured cells. Among the 74 mesothelioma patients with survival data, the group whose fluid contained IL-34 had significantly shorter survival than the rest, reported as 256 days versus 387 days (p=0.0044). IL-34 gene activity was higher in mesothelioma cells than in normal mesothelial cells, especially in cells with CDKN2A deletions. In three-dimensional cell clusters, mesothelioma cells led monocytes to become mostly 'M2-like' macrophages. These macrophages reduced the activity of tumour-targeting T cells by about 60%. A CSF-1R blocker, GW2580, partly restored that activity. The authors concluded the pathway is involved in the disease, but said larger studies are needed to confirm IL-34's value for predicting survival.

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 using stored patient samples (pleural effusions, tumour biopsies, primary cells and cell lines) with linked clinical data, plus a three-dimensional coculture (multicellular tumour spheroid) model
• Who was studied: Pleural effusions from 96 patients with malignant pleural mesothelioma, 105 with other neoplasia and 26 with benign pleural effusions, collected at the Laënnec Hospital (St-Herblain, France) between 1998 and 2016. Also 178 MPM tumours and 26 normal pleura biopsies, 69 primary MPM cell samples and 4 normal mesothelial cell samples, 30 MPM cell lines, and the TCGA-MESO dataset (87 patients)
• Exposure: The study measured the cytokines M-CSF and IL-34 and their genes (CSF1, IL34), not asbestos exposure. Confirmed asbestos exposure was recorded in 68.7% of MPM patients, 15.2% of other-neoplasia patients and 30.7% of benign-effusion patients in the pleural effusion study
• Main results:
  • Among MPM patients with survival data (74 patients), the group with IL-34 positive pleural effusion had significantly lower survival than the IL-34 negative group, reported as 256 days vs 387 days (p=0.0044); the article does not label these group figures as medians
  • The group of MPM patients with M-CSF levels above the mean had significantly lower survival than the others, reported as 238 days vs 387 days (p=0.0395)
  • In a multivariate analysis, IL-34 was an independent prognostic factor in the MPM cohort; histologic subtype (p=0.243) and M-CSF (p=0.218) did not reach significance
  • M-CSF was detectable in all pleural effusion types, with no significant difference between MPM, other neoplasia and benign groups; IL-34 was significantly higher in malignant than in benign effusions
  • In MPM tumours, CSF1 expression was correlated with macrophage markers, particularly of the M2-like subset (CD163, CD14); IL34 expression was not
  • IL34 gene expression, but not CSF1, was significantly higher in primary MPM cells (n=69) than in normal mesothelial cells (n=4), and was strongly associated mainly with biallelic CDKN2A deletions
  • In spheroids of Meso 34 mesothelioma cells with monocytes, approximately 85% of myeloid cells were CD14 high and CD163 high, which the authors interpreted as probably M2-like macrophages
  • With macrophages present in the spheroids, the cytotoxic activity of a tumour antigen-specific CD8+ T cell clone was reduced by approximately 60%
  • The CSF-1R inhibitor GW2580 reduced macrophage markers by approximately 50% and restored CD8+ T cell cytotoxicity from 40% up to 75%
• The authors' conclusion: The authors concluded that the M-CSF/IL-34/CSF-1R pathway is involved in MPM, that IL-34 could be a new prognostic biomarker, and that inhibiting the CSF-1R pathway could be a promising approach to favour the antitumour T cell response in patients with MPM
• Limitations the authors state:
  • The authors stated that larger cohorts are needed to confirm IL-34 as a prognostic biomarker
  • The authors noted strong dispersion of IL-34 values within groups, with fewer than 50% of samples positive for IL-34

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Tumor Microenvironment, Macrophage, Pleural Effusion, Cytokine, Mesothelial Cells, CDKN2A.

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