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Characterization of Tumor-Associated Macrophages and the Immune Microenvironment in Limited-Stage Neuroendocrine-High and -Low Small Cell Lung Cancer

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Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary
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Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Department of Tumor Biology, National Korányi Institute of Pulmonology, Piheno ut 1, 1121 Budapest, Hungary
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Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, 1122 Budapest, Hungary
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Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
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Institute of Digital Health Sciences, Faculty of Public Services, Semmelweis University, 1094 Budapest, Hungary
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Tisch Cancer Institute, Center for Thoracic Oncology, Mount Sinai Health System, New York, NY 1190, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Nadia Lampiasi
Biology 2021, 10(6), 502; https://doi.org/10.3390/biology10060502
Received: 27 April 2021 / Revised: 21 May 2021 / Accepted: 31 May 2021 / Published: 4 June 2021
(This article belongs to the Section Cancer Biology)
To date, the therapeutic strategy and guidelines in small cell lung cancer (SCLC) are based on cancer cell-related attributes with no biomarker used in the clinical practice. In the present study, using RNAseq and IHC, we aim to characterize in the frontline the latest biomarkers of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSC) and related critical elements, regulating the anti-tumor immune response. Accordingly, we extensively evaluated the TME associations in primary tumors and matched lymph node metastases in different tumor compartments (stroma and tumor nests) and neuroendocrine (NE) subtypes in limited-stage SCLC. We show the RNA gene enrichment of the most critical molecular pathways based on the Gene Ontology (GO) iteration system using thorough bioinformatics analysis to identify new molecular targets in distinct NE subtypes.
This study aims to characterize tumor-infiltrating macrophages (TAMs), myeloid-derived suppressor cells (MDSC), and the related molecular milieu regulating anti-tumor immunity in limited-stage neuroendocrine (NE)-high and NE-low small cell lung cancer. Primary tumors and matched lymph node (LN) metastases of 32 resected, early-stage SCLC patients were analyzed by immunohistochemistry (IHC) with antibodies against pan-macrophage marker CD68, M2-macrophage marker CD163, and MDSC marker CD33. Area-adjusted cell counting on TMAs showed that TAMs are the most abundant cell type in the TME, and their number in tumor nests exceeds the number of CD3 + T-cells (64% vs. 38% in NE-low and 71% vs. 18% in NE-high). Furthermore, the ratio of CD163-expressing M2-polarized TAMs in tumor nests was significantly higher in NE-low vs. NE-high tumors (70% vs. 31%). TAM density shows a strong positive correlation with CD45 and CD3 in tumor nests, but not in the stroma. fGSEA analysis on a targeted RNAseq oncological panel of 2560 genes showed that NE-high tumors exhibited increased enrichment in pathways related to cell proliferation, whereas in NE-low tumors, immune response pathways were significantly upregulated. Interestingly, we identified a subset of NE-high tumors representing an immune-oasis phenotype, but with a different gene expression profile compared to NE-low tumors. In contrast, we found that a limited subgroup of NE-low tumors is immune-deserted and express distinct cellular pathways from NE-high tumors. Furthermore, we identified potential molecular targets based on our expression data in NE-low and immune-oasis tumor subsets, including CD70, ANXA1, ITGB6, TP63, IFI27, YBX3 and CXCR2. View Full-Text
Keywords: SCLC; neuroendocrine subtype; macrophage; tumor microenvironment; fGSEA SCLC; neuroendocrine subtype; macrophage; tumor microenvironment; fGSEA
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MDPI and ACS Style

Dora, D.; Rivard, C.; Yu, H.; Pickard, S.L.; Laszlo, V.; Harko, T.; Megyesfalvi, Z.; Dinya, E.; Gerdan, C.; Szegvari, G.; Hirsch, F.R.; Dome, B.; Lohinai, Z. Characterization of Tumor-Associated Macrophages and the Immune Microenvironment in Limited-Stage Neuroendocrine-High and -Low Small Cell Lung Cancer. Biology 2021, 10, 502. https://doi.org/10.3390/biology10060502

AMA Style

Dora D, Rivard C, Yu H, Pickard SL, Laszlo V, Harko T, Megyesfalvi Z, Dinya E, Gerdan C, Szegvari G, Hirsch FR, Dome B, Lohinai Z. Characterization of Tumor-Associated Macrophages and the Immune Microenvironment in Limited-Stage Neuroendocrine-High and -Low Small Cell Lung Cancer. Biology. 2021; 10(6):502. https://doi.org/10.3390/biology10060502

Chicago/Turabian Style

Dora, David, Christopher Rivard, Hui Yu, Shivaun L. Pickard, Viktoria Laszlo, Tunde Harko, Zsolt Megyesfalvi, Elek Dinya, Csongor Gerdan, Gabor Szegvari, Fred R. Hirsch, Balazs Dome, and Zoltan Lohinai. 2021. "Characterization of Tumor-Associated Macrophages and the Immune Microenvironment in Limited-Stage Neuroendocrine-High and -Low Small Cell Lung Cancer" Biology 10, no. 6: 502. https://doi.org/10.3390/biology10060502

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