The role of the tumour microenvironment in the angiogenesis of pituitary tumours

Abstract

Purpose Angiogenesis has been studied in pituitary neuroendocrine tumours (PitNETs), but the role of the tumour microenvironment (TME) in regulating PitNET angiogenesis remains unknown. We aimed to characterise the role of TME components in determining the angiogenetic PitNET profile, focusing on immune cells and tumour-derived cytokines. Methods Immune cells were studied by immunohistochemistry in 24 human PitNETs (16 non-functioning-PitNETs (NF-PitNETs) and 8 somatotrophinomas): macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20) and neutrophils (neutrophil elastase); endothelial cells were assessed with CD31. Five normal pituitaries (NP) were included for comparison. Microvessel density and vascular morphology were estimated with ImageJ. The cytokine secretome from these PitNETs were assessed on culture supernatants using a multiplex immunoassay panel. Results Microvessel density/area was higher in NP than PitNETs, which also had rounder and more regular vessels. NF-PitNETs had vessels of increased calibre compared to somatotrophinomas. The M2:M1 macrophage ratio correlated with microvessel area. PitNETs with more CD4+ T cells had higher microvessel area, while tumours with more FOXP3+ cells were associated with lower microvessel density. PitNETs with more B cells had rounder vessels. Of the 42 PitNET-derived cytokines studied, CCL2, CXCL10 and CX3CL1 correlated with microvessel density and vessel architecture parameters. Conclusions M2 macrophages appear to play a role in PitNET neovascularisation, while B, CD4+ and FOXP3+ lymphocytes, as well as non-cellular TME elements such as CCL2, CXCL10 and CX3CL1, may also modulate the angiogenesis of PitNETs.

Towards precision medicine for clinically non‐functioning pituitary tumours

“…Several studies have found that tumour microenvironment elements, including immune and stromal cells, cytokines and growth factors within the extracellular matrix, influence pituitary tumour proliferation and invasion. 77,78 Identification of pituitary tumour immune signatures may give rise to expanded use of immune therapies, such as PDL-1 inhibitors. 79 In summary, several biomarkers have shown promise, in the research setting, as predictors of NFPT behaviour.…”

Research advances on the immune research and prospect of immunotherapy in pituitary adenomas

“…Recent studies by Zhang et al have shown that PA may produce excess lactate, resulting in TME acidification, which reshapes TAMs into an M2-type phenotype and then secrets CCL17 through TAMs to enhance tumor invasion through the CCL17/CCR4/mTORC1 axis [ 31 ]. Meanwhile, M2 macrophages may play a role in neoangiogenesis in pituitary adenomas together with B cells, CD4 + T cells, and Foxp3 + lymphocytes [ 32 ]. Dendritic cells (DCs) are the main antigen-presenting cells and serve as a bridge between adaptive and innate immune systems [ 33 ].…”

“…For example, the infiltration of CD8 + T cells was positively correlated with PRL and PRL and GH immunostaining in the tumor and was also positively correlated with the invasions of PAs [ 41 , 48 ]. The research of recent years has been recently reviewed by us and is presented in Table 1 [ 5 , 14 , 32 , 41 , 42 , 47 – 59 ]. It is worth noting that the role of immune cells in PAs is not yet clear and may vary among different tumor stages and types.…”

“…May have angiogenic effects. [ 32 , 41 , 48 , 49 ] 24; 134; 35; 48 Immunohistochemistry 2020 ;2020; 2015; 2016 CD8 (T cells) GH adenomas > non-GH adenomas. Positively correlated with serum PRL and intratumoral immunostaining of PRL and GH.…”

“…May have angiogenic effects. [ 32 , 52 ] 24; 115 Immunohistochemistry; RNA-seq. 2020; 2020 CD45 (lymphocytes) The CD45 staining in pituitary adenomas was significantly greater than that in normal pituitary.…”