GM-CSF derived from the inflammatory microenvironment potentially enhanced PD-L1 expression on tumor-associated macrophages in human breast cancer

Yonemitsu, Kimihiro; Pan, Cheng; Fujiwara, Yukio; Matsuda, Yuko; Shiota, Takuya; Yano, Hiromichi; Hosaka, Seiji; Tamada, Koji; Yamamoto, Yutaka; Komohara, Yoshihiro

doi:10.1038/s41598-022-16080-y

Cited by 17 publications

(17 citation statements)

References 47 publications

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“…40 A number of signaling pathways, including NF-κB and STAT pathways, are involved in PD-L1 expression. 29,30 In the current study, we found that the ERK signaling pathway was associated with PD-L1 expression in macrophages following MFC-exo treatment. After inhibiting the ERK signaling pathway, PD-L1 expression was significantly decreased in macrophages after MFC-exo stimulation.…”

Section: Discussionsupporting

confidence: 51%

“…PD‐L1 expression is mediated by genomic alterations, epigenetic modifications, transcriptional regulation, and posttranscriptional regulation and modification 40 . A number of signaling pathways, including NF‐κB and STAT pathways, are involved in PD‐L1 expression 29,30 . In the current study, we found that the ERK signaling pathway was associated with PD‐L1 expression in macrophages following MFC‐exo treatment.…”

Section: Discussionsupporting

confidence: 51%

“…It has been reported that several pathways, including NF‐κB, MAPK, and STAT3, mediate PD‐L1 expression in cancer cells and macrophages 29,30 . Hence, we investigated which potential signaling pathway was activated in macrophages following MFC‐exo stimulation.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that several pathways, including NF-κB, MAPK, and STAT3, mediate PD-L1 expression in cancer cells and macrophages. 29,30 Hence, we investigated which potential signaling pathway was activated in macrophages following MFC-exo stimulation. Western blots demonstrated there was a significant increase in p-ERK but no significant changes to p-PI3K, p-AKT, p-P65, p-JNK, p-P38, or p-STAT3 levels following MFCexo treatment, indicating the activation of ERK signaling but not the other pathways (Figure 5A).…”

Section: Mfc-exo Induce Pd-l1 Expression By Activating Extracellular-...mentioning

confidence: 99%

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Gastric cancer‐derived exosomes facilitate pulmonary metastasis by activating ERK‐mediated immunosuppressive macrophage polarization

Chu

Huo

et al. 2023

J of Cellular Biochemistry

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Gastric cancer (GC) with pulmonary metastasis is one of the deadliest diseases in the world; however, the underlying pathological mechanisms and potential therapeutic targets remain to be elucidated. As exosomes play indispensable roles in the formation of premetastatic niches (PMN) and cancer metastasis. Therefore, investigating the underlying mechanisms of exosome-mediated pulmonary metastasis of GC may shed new light on identifying novel therapeutic targets for GC treatment. GC-derived exosomes were isolated from the conditioned medium of mouse forestomach carcinoma (MFC) cell line. The effects of MFC-derived exosomes on pulmonary macrophage polarization were analyzed by reversetranscription polymerase chain reaction and flow cytometry. Expression of PD-L1 and other proteins was evaluated by Western blot. Exosomal microRNAs (miRNAs) were analyzed by microarray. GC-derived exosomes (GC-exo) accumulated in high numbers in the lungs and were ingested by macrophages. The extracellular-signalregulated kinase (ERK) signaling pathway was activated by GC-exo, inducing macrophage immunosuppressive-phenotype differentiation and increased PD-L1 expression. miRNA-sequencing identified 130 enriched miRNAs in GC-exo. Among the enriched miRNAs, miR-92a-3p plays a major role in activating ERK signaling via inhibition of PTEN expression. In addition, inhibiting ERK signaling with PD98059 significantly reduced the expression of PD-L1 in macrophages and, therefore, reversed the immunosuppressive PMN and inhibited the colonization of GC cells in the lungs. This study identified a novel mechanism of GC-exo mediated PD-L1 expression in lung macrophages that facilitates lung PMN formation and GC pulmonary metastasis, which also provided a potential therapeutic target for GC with pulmonary metastasis treatment.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionsupporting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Section: Mfc-exo Induce Pd-l1 Expression By Activating Extracellular-...mentioning

confidence: 99%

See 2 more Smart Citations

Gastric cancer‐derived exosomes facilitate pulmonary metastasis by activating ERK‐mediated immunosuppressive macrophage polarization

Chu

Huo

et al. 2023

J of Cellular Biochemistry

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“…Anti-GM-CSF therapy also inhibited the maturation and differentiation of TAMs. However, anti-GM-CSF therapy was ineffective against an E0771 breast cancer model [ 85 ]. This discrepancy might have been due to GM-CSF expression in tumor cells, since LLC cells express high levels of GM-CSF, whereas E0771 expresses no GM-CSF.…”

Section: Potential Immunotherapy Against Gm-csfmentioning

confidence: 99%

The Significance of SPP1 in Lung Cancers and Its Impact as a Marker for Protumor Tumor-Associated Macrophages

Matsubara

Yano

Pan

et al. 2023

Cancers

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Macrophages are a representative cell type in the tumor microenvironment. Macrophages that infiltrate the cancer microenvironment are referred to as tumor-associated macrophages (TAMs). TAMs exhibit protumor functions related to invasion, metastasis, and immunosuppression, and an increased density of TAMs is associated with a poor clinical course in many cancers. Phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional secreted phosphorylated glycoprotein. Although SPP1 is produced in a variety of organs, at the cellular level, it is expressed on only a few cell types, such as osteoblasts, fibroblasts, macrophages, dendritic cells, lymphoid cells, and mononuclear cells. SPP1 is also expressed by cancer cells, and previous studies have demonstrated correlations between levels of circulating SPP1 and/or increased SPP1 expression on tumor cells and poor prognosis in many types of cancer. We recently revealed that SPP1 expression on TAMs is correlated with poor prognosis and chemoresistance in lung adenocarcinoma. In this review, we summarize the significance of TAMs in lung cancers and discuss the importance of SPP1 as a new marker for the protumor subpopulation of monocyte-derived TAMs in lung adenocarcinoma. Several studies have shown that the SPP1/CD44 axis contribute to cancer chemoresistance in solid cancers, so the SPP1/CD44 axis may represent one of the most critical mechanisms for cell-to-cell communication between cancer cells and TAMs.

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Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer

Elfstrum,

Bapat,

Schwertfeger

2024

Cancer Medicine

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IntroductionMacrophages are innate immune cells that are associated with extensive phenotypic and functional plasticity and contribute to normal development, tissue homeostasis, and diseases such as cancer. In this review, we discuss the heterogeneity of tissue resident macrophages in the normal mammary gland and tumor‐associated macrophages in breast cancer. Tissue resident macrophages are required for mammary gland development, where they have been implicated in promoting extracellular matrix remodeling, apoptotic clearance, and cellular crosstalk. In the context of cancer, tumor‐associated macrophages are key drivers of growth and metastasis via their ability to promote matrix remodeling, angiogenesis, lymphangiogenesis, and immunosuppression.MethodWe identified and summarized studies in Pubmed that describe the phenotypic and functional heterogeneity of macrophages and the implications of targeting individual subsets, specifically in the context of mammary gland development and breast cancer. We also identified and summarized recent studies using single‐cell RNA sequencing to identify and describe macrophage subsets in human breast cancer samples.ResultsAdvances in single‐cell RNA sequencing technologies have yielded nuances in macrophage heterogeneity, with numerous macrophage subsets identified in both the normal mammary gland and breast cancer tissue. Macrophage subsets contribute to mammary gland development and breast cancer progression in differing ways, and emerging studies highlight a role for spatial localization in modulating their phenotype and function.ConclusionUnderstanding macrophage heterogeneity and the unique functions of each subset in both normal mammary gland development and breast cancer progression may lead to more promising targets for the treatment of breast cancer.

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GM-CSF derived from the inflammatory microenvironment potentially enhanced PD-L1 expression on tumor-associated macrophages in human breast cancer

Cited by 17 publications

References 47 publications

Gastric cancer‐derived exosomes facilitate pulmonary metastasis by activating ERK‐mediated immunosuppressive macrophage polarization

Gastric cancer‐derived exosomes facilitate pulmonary metastasis by activating ERK‐mediated immunosuppressive macrophage polarization

The Significance of SPP1 in Lung Cancers and Its Impact as a Marker for Protumor Tumor-Associated Macrophages

Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer

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