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Macrophage plasticity and function in the lung tumour microenvironment revealed in 3D heterotypic spheroid and explant models

Evans, Lauren, Milward, Kate ORCID:, Attanoos, Richard, Clayton, Aled ORCID:, Errington, Rachel ORCID: and Tabi, Zsuzsanna 2021. Macrophage plasticity and function in the lung tumour microenvironment revealed in 3D heterotypic spheroid and explant models. Biomedicines 9 (3) , 302. 10.3390/biomedicines9030302

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In non-small cell lung cancer (NSCLC), stroma-resident and tumour-infiltrating macrophages may facilitate an immunosuppressive tumour microenvironment (TME) and hamper immunotherapeutic responses. Analysis of tumour-associated macrophage (TAM) plasticity in NSCLC is largely lacking. We established a novel, multi-marker, dual analysis approach for assessing monocyte-derived macrophage (Mφ polarisation and M1/M2 phenotypic plasticity. We developed a flow cytometry-based, two-marker analysis (CD64 and CD206) of CD14+ cells. The phenotype and immune function of in vitro-induced TAMs was studied in a heterotypic spheroid and tumour-derived explant model of NSCLC. Heterotypic spheroids and NSCLC explants skewed Mφs from an M1- (CD206loCD64hi) to M2-like (CD206hiCD64lo) phenotype. Lipopolysaccharide (LPS) and IFNγ treatment reversed M2-like Mφ polarisation, indicating the plasticity of Mφs. Importantly, antigen-specific CD8+ T cell responses were reduced in the presence of tumour explant-conditioned Mφs, but not spheroid-conditioned Mφs, suggesting explants are likely a more relevant model of the immune TME than cell line-derived spheroids. Our data indicates the importance of multi-marker, functional analyses within Mφ subsets and the advantages of the ex vivo NSCLC explant model in immunomodulation studies. We highlight the plasticity of the M1/M2 phenotype using the explant model and provide a tool for studying therapeutic interventions designed to reprogram M2-like Mφ-induced immunosuppression.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This article is an open access article distributed under the terms and con‐ ditions of the Creative Commons At‐ tribution (CC BY) license (http://crea‐
Publisher: MDPI
ISSN: 2227-9059
Date of First Compliant Deposit: 17 March 2021
Date of Acceptance: 11 March 2021
Last Modified: 06 May 2023 05:02

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