<scp>CD68</scp>+ and <scp>CD8</scp>+ immune cells are associated with the growth pattern of somatotroph tumors and response to first generation somatostatin analogs

Chiloiro, Sabrina; Giampietro, Antonella; Gessi, Marco; Lauretti, Liverana; Mattogno, Pier Paolo; Cerroni, Lorenzo; Carlino, Angela; Alessandris, Quintino Giorgio De; Olivi, Alessandro; Rindi, Guido; Pontecorvi, Alfredo; Marinis, Laura De; Doglietto, Francesco; Bianchi, Antonio

doi:10.1111/jne.13263

Cited by 8 publications

(3 citation statements)

References 78 publications

(116 reference statements)

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“…Earlier studies often determined the proportion of macrophages by employing pan markers such as CD68, CD163, or CD204. These indicators investigated possible relationships between treatment response and tumor progression [ 60 ]. M2 macrophage infiltration is the primary immunological landscape that the PitNETs subtypes exhibit [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors

Lin,

Dai,

Han

et al. 2024

Genome Med

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Background Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has been widely recognized, the precise immunological environment and its control over tumor cells are poorly understood. Methods The heterogeneity, spatial distribution, and clinical significance of macrophages in PitNETs were analyzed using single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and multiplexed quantitative immunofluorescence (QIF). Cell viability, cell apoptosis assays, and in vivo subcutaneous xenograft experiments have confirmed that INHBA-ACVR1B influences the process of tumor cell apoptosis. Results The present study evaluated scRNA-seq data from 23 PitNET samples categorized into 3 primary lineages. The objective was to explore the diversity of tumors and the composition of immune cells across these lineages. Analyzed data from scRNA-seq and 365 bulk RNA sequencing samples conducted in-house revealed the presence of three unique subtypes of tumor immune microenvironment (TIME) in PitNETs. These subtypes were characterized by varying levels of immune infiltration, ranging from low to intermediate to high. In addition, the NR5A1 lineage is primarily associated with the subtype characterized by limited infiltration of immune cells. Tumor-associated macrophages (TAMs) expressing CX3CR1+, C1Q+, and GPNMB+ showed enhanced contact with tumor cells expressing NR5A1 + , TBX19+, and POU1F1+, respectively. This emphasizes the distinct interaction axes between TAMs and tumor cells based on their lineage. Moreover, the connection between CX3CR1+ macrophages and tumor cells via INHBA-ACVR1B regulates tumor cell apoptosis. Conclusions In summary, the different subtypes of TIME and the interaction between TAM and tumor cells offer valuable insights into the control of TIME that affects the development of PitNET. These findings can be utilized as prospective targets for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors

Lin,

Dai,

Han

et al. 2024

Genome Med

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“…Concerning the individual components of the TME, a tumor-infiltrating immune profile has been associated with poorer outcomes and recurrence in PitNETs [6]. Moreover, the identification of CD8+ T cells could predict the response to first-generation somatostatin analogs, regardless of tumor characteristics (hormone levels, size, and invasion) and patient age, as demonstrated by Chiloiro et al, where somatotropinomas with high levels of CD8+ and CD138+ lymphocytes responded to first-generation somatostatin analogs [45]. According to a recent study, anti-PD-L1 target therapy could act on those subgroups of PitNETs characterized by elevated Ki-67 and p53 values, with a higher percentage of tumorinfiltrating CD68+ macrophages and CD8+ TILs [46].…”

Section: Folliculo-stellate Cellsmentioning

confidence: 93%

Aggressive PitNETs and Potential Target Therapies: A Systematic Review of Molecular and Genetic Pathways

Serioli,

Agostini,

Pietrantoni

et al. 2023

IJMS

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Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine tumors) through the identification of specific essential genes, crucial molecular pathways, regulators, and effects of the tumoral microenvironment. Target therapies have been developed to cure oncology patients refractory to traditional treatments, introducing the concept of precision medicine. Preliminary data on PitNETs are derived from preclinical studies conducted on cell cultures, animal models, and a few case reports or small case series. This study comprehensively reviews the principal pathways involved in aggressive PitNETs, describing the potential target therapies. A search was conducted on Pubmed, Scopus, and Web of Science for English papers published between 1 January 2004, and 15 June 2023. 254 were selected, and the topics related to aggressive PitNETs were recorded and discussed in detail: epigenetic aspects, membrane proteins and receptors, metalloprotease, molecular pathways, PPRK, and the immune microenvironment. A comprehensive comprehension of the molecular mechanisms linked to PitNETs’ aggressiveness and invasiveness is crucial. Despite promising preliminary findings, additional research and clinical trials are necessary to confirm the indications and effectiveness of target therapies for PitNETs.

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“…Some authors reported increased CD8+ lymphocytes in invasive PitNETs [30,31]. Interestingly, CD8+ lymphocytes appear under-expressed in invasive or first-generation somatostatin analog-resistant somatotroph PitNETs [32,33]. In this respect, Marques P. et al showed that a low CD8:CD4 ratio is associated with increased tumor cell proliferation rather than an absolute decrease in CD8+ cells.…”

Section: Immune Cell Infiltratementioning

confidence: 99%

Role of Tumor Microenvironment in Pituitary Neuroendocrine Tumors: New Approaches in Classification, Diagnosis and Therapy

Tapoi,

Popa,

Tanase

et al. 2023

Cancers

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Adenohypophysal pituitary tumors account for 10–15% of all intracranial tumors, and 25–55% display signs of invasiveness. Nevertheless, oncology still relies on histopathological examination to establish the diagnosis. Considering that the classification of pituitary tumors has changed significantly in recent years, we discuss the definition of aggressive and invasive tumors and the latest molecular criteria used for classifying these entities. The pituitary tumor microenvironment (TME) is essential for neoplastic development and progression. This review aims to reveal the impact of TME characteristics on stratifying these tumors in view of finding appropriate therapeutic approaches. The role of the pituitary tumor microenvironment and its main components, non-tumoral cells and soluble factors, has been addressed. The variable display of different immune cell types, tumor-associated fibroblasts, and folliculostellate cells is discussed in relation to tumor development and aggressiveness. The molecules secreted by both tumoral and non-tumoral cells, such as VEGF, FGF, EGF, IL6, TNFα, and immune checkpoint molecules, contribute to the crosstalk between the tumor and its microenvironment. They could be considered potential biomarkers for diagnosis and the invasiveness of these tumors, together with emerging non-coding RNA molecules. Therefore, assessing this complex network associated with pituitary neuroendocrine tumors could bring a new era in diagnosing and treating this pathology.

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CD68+ and CD8+ immune cells are associated with the growth pattern of somatotroph tumors and response to first generation somatostatin analogs

Abstract: Somatotropinomas are pituitary tumors with a heterogenous clinical behavior. The tumor microenvironment regulates the interaction between tumor cells and the host immune system, potentially modulating tumor behavior. Here, we aimed to investi-

Cited by 8 publications

References 78 publications

Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors

Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors

Aggressive PitNETs and Potential Target Therapies: A Systematic Review of Molecular and Genetic Pathways

Role of Tumor Microenvironment in Pituitary Neuroendocrine Tumors: New Approaches in Classification, Diagnosis and Therapy

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