Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications.
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ABSTRACT:
SUBMITTER: Rihawi K
PROVIDER: S-EPMC8067563 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor-associated macrophages (TAMs), representing most of the leukocyte population in solid tumors, demonstrate great phenotypic heterogeneity and diverse functional capabilities under the influence of the local tumor microenvironment. These anti-inflammatory and protumorigenic macrophages modulate the local microenvironment to facilitate tumor growth and metastasis. In this review, we examine the origin of TAMs and the complex regulatory networks within the tumor microenvironment that facilitate the polarization of TAMs toward a protumoral phenotype. More extensively, we evaluate the mechanisms by which TAMs mediate angiogenesis, metastasis, chemotherapeutic resistance and immune evasion. Lastly, we will highlight novel interventional strategies targeting TAMs in preclinical studies and in early clinical trials that have significant potential in improving efficacy of current chemotherapeutic and/or immunotherapeutic approaches.
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Project description:Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs.
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Project description:BackgroundKynureninase (KYNU) is a potential prognostic marker for various tumor types. However, no reports on the biological effects and prognostic value of KYNU in gastric cancer (GC) exist.MethodsGC-associated single-cell RNA sequencing and bulk RNA sequencing (bulk-seq) data were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. The differential expression of KYNU between GC and normal gastric tissues was first analyzed based on the bulk-seq data, followed by an exploration of the relationship between KYNU and various clinicopathological features. The Kaplan-Meier survival and Cox regression analyses were performed to determine the prognostic value of KYNU. The relationship between KYNU expression and immune cell infiltration and immune checkpoints was also explored. The biological function of KYNU was further examined at the single-cell level, and in vitro experiments were performed to examine the effect of KYNU on GC cell proliferation and invasion.ResultsKYNU expression was significantly elevated in GC samples. Clinical features and survival analysis indicated that high KYNU expression was associated with poor clinical phenotypes and prognosis, whereas Cox analysis showed that KYNU was an independent risk factor for patients with GC. Notably, high expression of KYNU induced a poor immune microenvironment and contributed to the upregulation of immune checkpoints. KYNU-overexpressing macrophages drove GC progression through unique ligand-receptor pairs and transcription factors and were associated with adverse clinical phenotypes in GC. KYNU was overexpressed in GC cells in vitro, and KYNU knockout significantly inhibited GC cell proliferation and invasion.ConclusionHigh KYNU expression promotes an adverse immune microenvironment and low survival rates in GC. KYNU and KYNU-related macrophages may serve as novel molecular targets in the treatment of GC.
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Project description:Inflammatory breast cancer (IBC) is a rare and very aggressive subtype of breast cancer with clinical manifestations similar to acute inflammation. The prognosis of IBC is still poor even though combination therapy with surgery, chemotherapy, and target therapy, mainly due to a lack of fully understanding of the cellular and molecular mechanisms of IBC pathogenesis and progression. In the present article, we have comprehensively reviewed the connection of the pathogenesis of IBC and inflammation, immune reaction and cancer, particularly focused on the role and mechanism of tumor microenvironment related to IBC formation, tumor cell proliferation, migration, invasion and metastasis as well as the clinical manifestations of IBC. As the diverse cells including inflammatory cells, immune cells, and tumor cells and the soluble molecules produced by these cells in the microenvironment play an essential role in IBC development and progression. Therefore, anti-inflammatory therapy and immunotherapy with available agents warrant further investigation in the treatment of IBC.
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Project description:A large number of immune cells are present in the tumour microenvironment (TME), of which, tumour-associated macrophages (TAMs) are among the most important and highly infiltrated cells, and mainly include the M1 type classically activated and M2 type alternatively activated TAMs. Both cell types are known to play an important role in tumour initiation and proliferation. It has recently been confirmed that the TAMs in tumours tend to be dominated by the M2 type. However, the precise mechanism underlying TAM recruitment and polarization in the immune microenvironment remains to be elucidated. The Hippo-Yes-associated protein (YAP) signalling pathway is one of the most extensively discussed mechanism for the regulation of tumour proliferation, migration, angiogenesis, and invasion in recent years. To date, several studies have revealed that YAP is involved in the interrelating interactions between tumour and immune cells, particularly the TAMs. In this review, we have summarized the mechanism by which the YAP regulates the activity of TAMs and its impact on the TME.
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Project description:Gastric adenocarcinoma is one of the most common types of cancer worldwide, with an incidence of a million new cases annually. In addition to having a high mortality rate due to often delayed detection and its poor response to cancer therapy, it also spreads aggressively. Inflammation has been shown to play a role in carcinogenesis. Consequently, macrophages are important in phagocytosis, antigen presenting and producing cytokines and growth factors. As a response to microenvironmental signals, they may polarize into tumor resisting M1 or tumor promoting M2 macrophages. Recently, studies have indicated that M2-type macrophage resembling tumor-associated macrophages (TAMs) might be used as an independent prognostic factor for gastric cancer. This review will discuss the possible use of TAMs as prognostic tools for gastric cancer and whether they are suitable for use in clinical environment.
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Project description:Tumor microenvironment and heterogeneity play vital roles in the development and progression of gastric cancer (GC). In the past decade, a considerable amount of single-cell RNA-sequencing (scRNA-seq) studies have been published in the fields of oncology and immunology, which improve our knowledge of the GC immune microenvironment. However, much uncertainty still exists about the relationship between the macroscopic and microscopic data in transcriptomics. In the current study, we made full use of scRNA-seq data from the Gene Expression Omnibus database (GSE134520) to identify 25 cell subsets, including 11 microenvironment-related cell types. The MIF signaling pathway network was obtained upon analysis of receptor-ligand pairs and cell-cell interactions. By comparing the gene expression in a wide variety of cells between intestinal metaplasia and early gastric cancer, we identified 64 differentially expressed genes annotated as immune response and cellular communication. Subsequently, we screened these genes for prognostic clinical value based on the patients' follow-up data from The Cancer Genome Atlas. TMPRSS15, VIM, APOA1, and RNASE1 were then selected for the construction of LASSO risk scores, and a nomogram model incorporating another five clinical risk factors was successfully created. The effectiveness of least absolute shrinkage and selection operator risk scores was validated using gene set enrichment analysis and levels of immune cell infiltration. These findings will drive the development of prognostic evaluations affected by the immune tumor microenvironment in GC.
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Project description:The tumor-adipose microenvironment (TAME) is a universal microecosystem, that is characterized by the dysfunction of lipid metabolism, such as excessive free fatty acids (FFAs). Macrophages are the most abundant immune cell type within TAME, although their diversity in the TAME is not clear. We first reveal that infiltration of M2-like macrophages in the TAME is associated with poor survival in breast cancer. To explore lipid-associated alterations in the TAME, we also detected the levels of FFAs transporters including fatty acid binding proteins (FABPs) and fatty acid transport protein 1 (FATP1). The results indicated that expression of fatty acid transporters in the TAME is tightly linked to the function of macrophages and predicts survival in breast cancer. To explore the impact of FFAs transporters on the function of macrophages, we performed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. Consequently, we identified a special subpopulation of macrophages defined as lipid-associated macrophages (LAMs), highly expressed macrophage markers (CD163, SPP1 and C1QC), genes involved in lipid metabolism (FABP3, FABP4, FABP5, LPL and LIPA) and some lipid receptors (LGALS3 and TREM2). Functionally, LAMs were characterized by a canonical functional signature of M2-like macrophages, lipid accumulation and enhancing phagocytosis, and they were mostly distributed in tumor-adipose junctional regions. Finally, the allograft cancer mouse models confirmed that LAMs depletion in the TAME synergizes the antitumorigenic effects of anti-PD1 therapy. In summary, we defined a novel subtype of macrophages in the TAME, that has unique features and clinical outcomes.
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