The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma

Our plain-English summary of The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma, by C. Laberiano-Fernandez, C.M. Baldavira, J. Machado-Rugolo, et al (Cancers, 2023).

The study

• Authors: C. Laberiano-Fernandez, C.M. Baldavira, J. Machado-Rugolo, A. Tamegnon, R.K. Pandurengan, A.M. Ab'Saber, M.L. Balancin, T.Y. Takagaki, M.A. Nagai, V.L. Capelozzi, E.R. Parra
• Journal: Cancers
• Published: 2023;15(21)
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design.

Methods: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments.

Results: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors.

Conclusions: The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.

In plain English

This laboratory study examined macrophages, a type of immune cell, in malignant pleural mesothelioma. The authors analyzed gene data on 87 mesothelioma cases from The Cancer Genome Atlas. They then stained tumor tissue from 68 patients diagnosed in São Paulo, Brazil, to count macrophage types and measure their distance from cancer cells. Asbestos exposure was recorded for 37 of the 68 patients; fiber types were not reported. M2-type macrophages predominated. Exposed patients had significantly higher densities of two M2 subtypes (p = 0.006 and p = 0.008). Their macrophages overall lay farther from cancer cells (median 104.34 versus 57.81 micrometers in unexposed patients, p = 0.006). In a survival model, lower densities of one M2 subtype went with better survival (hazard ratio 0.135, 95% CI 0.022 to 0.827), and lower densities of another went with worse survival (7.079, 95% CI 1.442 to 34.743). Asbestos exposure was not significantly linked to survival (1.179, 95% CI 0.415 to 3.351). The authors concluded that macrophages, particularly CD206+ ones, are highly relevant to patient outcomes. They noted the tissue sampling format and small case numbers as limitations.

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: Two-stage laboratory study: a computational analysis of public gene data (The Cancer Genome Atlas) as a discovery cohort, then a validation cohort of patient tumor tissue stained by multiplex immunofluorescence on tissue microarrays
• Who was studied: Discovery: 87 malignant mesothelioma cases in The Cancer Genome Atlas. Validation: 68 patients with malignant pleural mesothelioma diagnosed at the Hospital das Clínicas complex, University of São Paulo, Brazil (47 male, 21 female; median age 58; 58 epithelioid, 10 sarcomatoid). No study dates are given.
• Exposure: The main variables were macrophage types, their densities and their distances from cancer cells. Asbestos exposure was recorded only as yes (37) or no (31); no fiber types, products, jobs or doses are given.
• Main results:
  • In the 68 tissue samples, the authors found an increase in immunosuppressive M2-like macrophages that did not extend to M1-like macrophages.
  • Patients with asbestos exposure had significantly higher densities of M2a (CD68+CD163+Arg-1+) and M2c (CD68+CD163+CD206+Arg-1neg) macrophages than patients without exposure (p = 0.006 and p = 0.008).
  • Overall (CD68+) macrophages were closer to cancer cells in patients without asbestos exposure: median distance 104.34 µm in the asbestos group versus 57.81 µm in the non-asbestos group (p = 0.006).
  • In the Cox model adjusted for histology, asbestos exposure and overall macrophage distance, low versus high density of M2 CD68+CD206+MRP8-14negCD86neg macrophages had HR 0.135 (95% CI 0.022 to 0.827, p = 0.030), described as better survival.
  • In the same model, low versus high density of M2 CD68+CD163+CD206+MRP8-14negCD86neg macrophages had HR 7.079 (95% CI 1.442 to 34.743, p = 0.016), described as worse survival.
  • In the same model, asbestos exposure (yes vs. no) had HR 1.179 (95% CI 0.415 to 3.351, p = 0.758), not statistically significant.
  • In univariate analysis of the 68 patients, above-median density of all CD68+ macrophages was associated with better overall survival.
  • In the Cancer Genome Atlas data, high NOS2, INHBA and FN1 gene expression was associated with worse overall survival.
• The authors' conclusion: The authors concluded that macrophages in the tumor, particularly CD206+ macrophages, are highly relevant to patient outcomes.
• Limitations the authors state:
  • Tissue microarray samples may under- or overrepresent marker levels and spatial distribution because of tumor heterogeneity, and the cohort had a small number of cases.
  • In the Cancer Genome Atlas analysis by lymph node status, only three cases had N3 staging.

Topics

Medical terms in this study, explained in our Lexicon: Macrophage, Pleural Mesothelioma, Discovery, Paraffin Block, Tumor Microenvironment, Prognosis, Overall Survival.

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