Analysis of Tumor Angiogenesis and Immune Microenvironment in Non-Functional Pituitary Endocrine Tumors

Sato, Mizuto; Tamura, Ryota; Tamura, Haruka; Mase, Taro; Kosugi, Kenzo; Morimoto, Yukina; Yoshida, Kazunari; Toda, Masahiro

doi:10.3390/jcm8050695

Cited by 62 publications

(67 citation statements)

References 57 publications

(76 reference statements)

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“…These findings support a role for infiltrating M2-macrophages in the angiogenesis of PitNETs, as previously described in other cancers [13, 27, 42, 44, 80, 83]. We found no association between PitNET-infiltrating CD163+ macrophages and cavernous sinus invasion, although a recent study showed more CD163+ macrophages in invasive NF-PitNETs than in non-invasive tumours [68].…”

Section: Discussionsupporting

confidence: 92%

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Marques

Barry

Carlsen³

et al. 2019

acta neuropathol commun

105

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Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n = 5). In vitro tumour–macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs (p < 0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes (p = 0.005), but fewer neutrophils (p = 0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas (p = 0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with “deleterious immune phenotype” (CD68hiCD4hiFOXP3hiCD20hi) had a Ki-67 ≥ 3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density (p = 0.015) and area (p < 0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.

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Section: Discussionsupporting

confidence: 92%

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Marques

Barry

Carlsen³

et al. 2019

acta neuropathol commun

105

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“…Programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) is a pair of negative costimulatory factors that play a key role in the tumor immune escape mechanism. PD-L1 can be expressed in tumor microenvironment cells and can inhibit the activation of T cells through binding to PD-1, which also weakens the entire immune system of patients [33][34][35]. Immune checkpoint therapy prevents PD-1/PD-L1 binding in tumors and restores the cytotoxicity of T cells [36].…”

Section: Discussionmentioning

confidence: 99%

Second-line treatment strategy for urothelial cancer patients who progress or are unfit for cisplatin therapy: a network meta-analysis

Wang

Liu

Fang

et al. 2019

Preprint

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Background Second-line treatment for urothelial carcinoma (UC) patients is used if progression or failure after platinum-based chemotherapy occurs or if patients are cisplatin-unfit. However, there is still no widely accepted treatment strategy. We aimed to analyze the effectiveness and safety of second-line treatment strategies for UC patients. Methods The PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) that included UC patients who were cisplatin-ineligible or unfit up to April 19, 2019. The primary outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Results Thirteen trials that assessed 3502 UC patients were included. This study divided the network comparisons into three parts. The first part contained studies comparing taxanes and other interventions; the second part assessed investigator’s choice chemotherapy (ICC)-related comparisons; and the third part assessed best support care (BSC). In the OS results of the first part, pembrolizumab (87.5%), ramucirumab plus docetaxel (74.6%), and atezolizumab (71.1%) had a relative advantage. Pembrolizumab also had advantages in ORR and severe adverse effect (SAE) results. Vinflunine and ramucirumab plus docetaxel had a relatively high surface under the cumulative ranking (SUCRA) rank by exploratory cluster analysis. Conclusions This study concluded that atezolizumab and pembrolizumab are superior to other treatments, mainly in OS results, but no treatment confers a significant advantage in PFS. Pembrolizumab still has relative advantages in ORR and SAE results compared to ICC.

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“…As such, the immune TME needs to be carefully characterized in the different groups of pituitary tumors prior to understanding its exact role. To date, studies aimed at defining the immune TME of pituitary tumors are rare and mostly rely on the immunohistological characterization of cells based on a single or a few immune markers that are not sufficient to define the complexity of immune cell lineages (Table 2) [37,38,39,40,41,42,43,44]. Moreover, the classification of pituitary tumors (including the use of IHC for diagnosis) and of their aggressiveness varies across different studies, as does the interpretation of the immune infiltrate, with some studies considering the immune infiltrate in terms of either its presence or absence, while other studies have looked at the quantity or the intensity of the various markers.…”

Section: Immune Infiltrative Cellsmentioning

confidence: 99%

“…Therefore, the combined use of immunotherapies and drugs targeting angiogenesis is emerging as a novel strategy for the treatment of numerous cancers [8,49]. Interestingly, such observations may also have important implications for the treatment of pituitary tumors as it was recently reported that pituitary tumors invading the cavernous sinus show a higher expression of VEGF, VEGFR1, and PD-L1, as well as having a higher number of TAMs [44]. This suggests that, at least in the case of the aggressive non-functioning pituitary tumors analyzed in their study, tumor angiogenesis is associated with an immunosuppressive TME, and that immunotherapy combined with therapies aimed at obtaining vascular normalization should be envisioned in such tumor types.…”

Section: Immune Infiltrative Cellsmentioning

confidence: 99%

The Microenvironment of Pituitary Tumors—Biological and Therapeutic Implications

Ilie

Vasiljevic

Raverot

et al. 2019

Cancers

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The tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors. This review summarizes our current knowledge of the TME within pituitary tumors and the strong interest in TME as a therapeutic target. While we cover the importance of angiogenesis and immune infiltrating cells, we also address the role of the elusive folliculostellate cells, the emerging literature on pituitary tumor-associated fibroblasts, and the contribution of extracellular matrix components in these tumors. The cases of human pituitary tumors treated with TME-targeting therapies are reviewed and emerging concepts of vascular normalization and combined therapies are presented. Together, this snapshot overview of the current literature pinpoints not only the underestimated role of TME components in pituitary tumor biology, but also the major promise it may offer for both prognosis and targeted therapeutics.

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Analysis of Tumor Angiogenesis and Immune Microenvironment in Non-Functional Pituitary Endocrine Tumors

Cited by 62 publications

References 57 publications

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Second-line treatment strategy for urothelial cancer patients who progress or are unfit for cisplatin therapy: a network meta-analysis

The Microenvironment of Pituitary Tumors—Biological and Therapeutic Implications

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