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

Caddie Laberiano-Fernandez; Camila Machado Baldavira; Juliana Machado-Rugolo; Auriole Tamegnon; Renganayaki Krishna Pandurengan; Alexandre Muxfeldt Ab'Saber; Marcelo Luiz Balancin; Teresa Yae Takagaki; Maria Aparecida Nagai; Vera Luiza Capelozzi; Edwin Roger Parra

doi:10.3390/cancers15215116

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

Cancers (Basel). 2023 Oct 24;15(21):5116. doi: 10.3390/cancers15215116.

Authors

Affiliations

¹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Pathology, Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil.
³ Division of Pneumology, Instituto do Coração (Incor), Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil.
⁴ Department of Radiology and Oncology, Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil.
⁵ Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of Sao Paulo, Sao Paulo 01246-903, Brazil.

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.

Keywords: in silico analysis; malignant pleural mesothelioma; multiplex immunofluorescence; prognosis; transcriptoma.

Grants and funding

Support for the study was partially provided by the Multiplex Immunofluorescence and Image Analysis Laboratory (MIIAL) at the Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center; the Sao Paulo Research Foundation (FAPESP; 2018/20403-6, 2019/12151-0 and 2023/02755-0); the National Council for Scientific and Technological Development (CNPq; 303735/2021-0); and the University of Sao Paulo Medical School, Sao Paulo, Brazil.