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Endocrine Abstracts (2019) 63 OC13.3 | DOI: 10.1530/endoabs.63.OC13.3

ECE2019 Oral Communications Anterior and Posterior pituitary 2 (5 abstracts)

Pituitary tumour-derived chemokines modulate immune cell infiltrates in the tumour microenvironment leading to aggressive phenotype

Pedro Marques 1 , Sayka Barry 1 , Eivind Carlsen 2 , David Collier 1 , Amy Ronaldson 1 , Sherine Awad 1 , Nigel Mendoza 3 , Neil Dorward 4 , Joan Grieve 4 , Frances Balkwill 5 & Márta Korbonits 1

1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2Department of Pathology, STHF, Skien, Norway; 3Department of Neurosurgery, Imperial College Healthcare NHS Trust, London, UK; 4The National Hospital for Neurology and Neurosurgery, UCLH, NHS Trust, London, UK; 5Barts Cancer Institute, Queen Mary University of London, London, UK.

Introduction: Tumour microenvironment (TME) is determined by non-tumoral cells, including immune, stromal or endothelial cells, and influences tumorigenesis, proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary adenomas (PAs). We aimed to characterise the TME of PAs and its role in their aggressiveness, focusing on PA-infiltrating immune cells and cytokine network.

Methods: Cytokine secretome from 24 human PAs (16NFPAs, 8GHomas) was assessed on primary culture supernatants using a multiplex immunoassay panel with 42 cytokines. These data were compared to immunohistochemical analysis of the same tumours assessing endothelial cells (CD31), macrophages (CD68), ‘M2’-macrophages (CD163), ‘M1’-macrophages (HLA-DR), cytotoxic T lymphocytes (CD8), T helper lymphocytes (CD4), T regulatory cells (FOXP3), B cells (CD20) and neutrophils (neutrophil elastase), and 5 normal pituitaries were studied for comparison.

Results: The cytokine array identified IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 as the main PA-derived cytokines. PAs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels, while CD8+T lymphocyte PA-infiltration was associated with higher CCL2, CCL4 and VEGF-A levels. No significant associations between PA-derived cytokines and CD4+T, FOXP3+ and B cells were noted. PA immune cell infiltrates differ from normal pituitary: PAs contained more CD68-macrophages (4.6±0.4 vs 1.2±0.2%, P<0.001), with a 3-fold increased M2:M1 macrophage ratio, more CD4+T cells (1.0±0.1 vs 0.6±0.1%, P=0.005), but fewer neutrophils (0.7±0.2 vs 1.4±0.1%, P=0.047) and a trend for fewer CD8+T cells (1.8±0.2 vs 2.6±0.3%, P=0.077) with a 2-fold decreased CD8:CD4 T cell ratio. NFPAs had significantly more neutrophils than GHomas (0.9±0.1 vs 0.1±0.1%, P=0.002), but there were no differences regarding other immune cell subpopulations. PA-infiltrating immune cells did not correlate with the respective serum immune cell subpopulations, suggesting differential recruitment into the PA rather than altered bone marrow production. PAs with higher Ki67 had a higher amount of FOXP3+T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 cell ratios. All PAs with deleterious immune infiltrate phenotype (CD68hiCD4hiFOXP3hiCD20hi) had Ki67≥3%. M2:M1 ratio was positively correlated with microvessel density (P=0.015) and area (P<0.001).

Conclusions: PAs are primarily infiltrated by macrophages with an increased M2:M1 ratio compared with normal pituitary, but also have reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PA-derived chemokines (IL-8, CCL2, CCL3, CCL4 and CXCL1) facilitate macrophage, neutrophil and T cell recruitment into the tumour, and our data suggest that this modulation of immune cell infiltrates in the TME determines increased aggressiveness.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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