Macrophages in Osteosarcoma Immune Microenvironment: Implications for Immunotherapy

Luo, Zhenguo; Li, Panpan; Wang, Zhenxing; Chen, Chun-Yuan; Xie, Hui

doi:10.3389/fonc.2020.586580

Cited by 53 publications

(53 citation statements)

References 143 publications

(206 reference statements)

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“… 29 A higher proportion of M2 macrophages is associated with a poorer prognosis, while the M1 population can enhance tumor-killing effects. 30 , 31 We observed a significant increase in M1 macrophages in the tumors from Akk -EVs-treated mice (representative image in Figure 3C and statistical analysis in Figure 3D : P = 0.0155), as well as a decrease in M2 macrophages ( P = 0.0318; Figure 3E ), while the proportion of an intermediate state of macrophages (expressing both MHC-II and CD206) remained unchanged ( P = 0.4425; Figure 3F ). We also examined the populations of macrophages in the peripheral blood.…”

Section: Resultsmentioning

confidence: 99%

“… 3 , 11 , 50 Macrophages are highly plastic and heterogeneous cells, and the M1 and M2 phenotypes represent the two distinct termini of the macrophage activation spectrum. 31 , 51 Generally, M1 macrophages have tumoricidal activity by producing inflammatory cytokines and activating the immune response. 52 , 53 On the other hand, local signals in the TME activate M2 macrophages to trigger tumor neovascularization, immunosuppression, and tumor extracellular matrix reorganization, contributing to PCa progression.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular Vesicles from Akkermansia muciniphila Elicit Antitumor Immunity Against Prostate Cancer via Modulation of CD8+ T Cells and Macrophages

Luo¹,

Xia²,

Liu³

et al. 2021

IJN

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Purpose Prostate cancer (PCa) is one of the most common malignancies in males. Despite the success of immunotherapy in many malignant cancers, strategies are still needed to improve therapeutic efficacy in PCa. This study aimed to investigate the effects of Akkermansia muciniphila -derived extracellular vesicles ( Akk -EVs) on PCa and elucidate the underlying immune-related mechanism. Methods Akk -EVs were isolated by ultracentrifugation and intravenously injected to treat syngeneic PCa-bearing immune-competent mice. Immunophenotypic changes in immune cells, such as cytotoxic T lymphocytes and macrophages, were measured via flow cytometry analysis. Histological examination was used to detect morphological changes in major organs after Akk -EVs treatments. In vitro, flow cytometry was performed to confirm the effects of Akk -EVs on the activation of CD8 + T cells. Quantitative PCR and immunofluorescence staining were carried out to test the impact of Akk -EVs on macrophage polarization. Cell counting kit-8 (CCK-8) analysis, colony formation assays, and scratch wound healing assays were conducted to assess the effects of Akk -EVs-treated macrophages on the proliferation and invasion of PCa cells. CCK-8 assays also confirmed the impact of Akk -EVs on the viability of normal cells. Results Intravenous injection of Akk -EVs in immune-competent mice reduced the tumor burden of PCa without inducing obvious toxicity in normal tissues. This treatment elevated the proportion of granzyme B-positive (GZMB + ) and interferon γ-positive (IFN-γ + ) lymphocytes in CD8 + T cells and caused macrophage recruitment, with increased tumor-killing M1 macrophages and decreased immunosuppressive M2 macrophages. In vitro, Akk -EVs increased the number of GZMB + CD8 + and IFN-γ + CD8 + T cells and M1-like macrophages. In addition, conditioned medium from Akk -EVs-treated macrophages suppressed the proliferation and invasion of prostate cells. Furthermore, the effective dose of Akk -EVs was well-tolerated in normal cells. Conclusion Our study revealed the promising prospects of Akk -EVs as an efficient and biocompatible immunotherapeutic agent for PCa treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles from Akkermansia muciniphila Elicit Antitumor Immunity Against Prostate Cancer via Modulation of CD8+ T Cells and Macrophages

Luo¹,

Xia²,

Liu³

et al. 2021

IJN

Self Cite

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“…In tumor microenvironment, tumor infiltrating immune cells account for the primary non-tumor constituents, which have been demonstrated to play an important role in prognostic prediction of OS patients (Zhang et al, 2020). Thus, TIME takes crucial significance in the development and progression of tumor, and accumulated evidence revealed that TIME was closely associated with pathogenesis of osteosarcoma (Heymann et al, 2019;Luo et al, 2020). Assessing the TIME of osteosarcoma helps to understand the immune status of tumor cells, is conducive to promote the development of immunotherapy and improve the prognosis of osteosarcoma patients.…”

Section: Introductionmentioning

confidence: 99%

Expression of Lipid-Metabolism Genes Is Correlated With Immune Microenvironment and Predicts Prognosis in Osteosarcoma

Lei

et al. 2021

Front. Cell Dev. Biol.

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ObjectivesOsteosarcoma was the most popular primary malignant tumor in children and adolescent, and the 5-year survival of osteosarcoma patients gained no substantial improvement over the past 35 years. This study aims to explore the role of lipid metabolism in the development and diagnosis of osteosarcoma.MethodsClinical information and corresponding RNA data of osteosarcoma patients were downloaded from TRGET and GEO databases. Consensus clustering was performed to identify new molecular subgroups. ESTIMATE, TIMER and ssGSEA analyses were applied to determinate the tumor immune microenvironment (TIME) and immune status of the identified subgroups. Functional analyses including GO, KEGG, GSVA and GSEA analyses were conducted to elucidate the underlying mechanisms. Prognostic risk model was constructed using LASSO algorithm and multivariate Cox regression analysis.ResultsTwo molecular subgroups with significantly different survival were identified. Better prognosis was associated with high immune score, low tumor purity, high abundance of immune infiltrating cells and relatively high immune status. GO and KEGG analyses revealed that the DEGs between the two subgroups were mainly enriched in immune- and bone remodeling-associated pathways. GSVA and GSEA analyses indicated that, lipid catabolism downregulation and lipid hydroxylation upregulation may impede the bone remodeling and development of immune system. Risk model based on lipid metabolism related genes (LMRGs) showed potent potential for survival prediction in osteosarcoma. Nomogram integrating risk model and clinical characteristics could predict the prognosis of osteosarcoma patients accurately.ConclusionExpression of lipid-metabolism genes is correlated with immune microenvironment of osteosarcoma patients and could be applied to predict the prognosis of in osteosarcoma accurately.

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“…Macrophage M1 contributes to tumor elimination and M2 serves as a promoter in tumorigenesis. Contrary to the cancer-promoting role of macrophages in a wide range of cancers, the high density of macrophages indicates longer survival in osteosarcoma [13]. However, there is a lack of systematic analysis of the heterogeneity of infiltrating immune cells in metastatic osteosarcoma.…”

Section: Introductionmentioning

confidence: 97%

“…Several reports have indicated that infiltrating immune cells were positively correlated with better clinical survival [9,10]. While Chen et al and Koirala et al have reported the opposite conclusion that the infiltrating immune cells act as a risk factor for osteosarcoma [11,12], M1 and M2 phenotypes were two polarized terminals of the macrophages that exhibit opposite functions in antitumor response [13]. Macrophage M1 contributes to tumor elimination and M2 serves as a promoter in tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

The Heterogeneity of Infiltrating Macrophages in Metastatic Osteosarcoma and Its Correlation with Immunotherapy

Wang

Chen

et al. 2021

Journal of Oncology

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Background. Metastatic osteosarcoma is a common and fatal bone tumor. Several studies have found that tumor-infiltrating immune cells play pivotal roles in the progression of metastatic osteosarcoma. However, the heterogeneity of infiltrating immune cells across metastatic and primary osteosarcoma remains unclear. Methods. Immune infiltration analysis was carried out via the “ESTIMATE” and “xCell” algorithms in primary and metastatic osteosarcoma. Then, we evaluated the prognostic value of infiltrating immune cells in 85 osteosarcomas through the Kaplan–Meier (K-M) and receiver operating characteristic (ROC) curve. Infiltrations of macrophage M1 and M2 were evaluated in metastatic osteosarcoma, as well as their correlation with immune checkpoints. Macrophage-related prognostic genes were identified through Weighted Gene Coexpression Network Analysis (WGCNA), Lasso analysis, and Random Forest algorithm. Finally, a macrophage-related risk model had been constructed and validated. Results. Macrophages, especially the macrophage M1, sparingly infiltrated in metastatic compared with the primary osteosarcoma and predicted the worse overall survival (OS) and disease-free survival (DFS). Macrophage M1 was positively correlated with immune checkpoints PDCD1, CD274 (PD-L1), PDCD1LG2, CTLA4, and TIGIT. In addition, four macrophage-related prognostic genes (IL10, VAV1, CD14, and CCL2) had been identified, and the macrophage-related risk model had been validated to be reliable for evaluating prognosis in osteosarcoma. Simultaneously, the risk score showed a strong correlation with several immune checkpoints. Conclusion. Macrophages potentially contribute to the regulation of osteosarcoma metastasis. It can be used as a candidate marker for metastatic osteosarcoma’ prognosis and immune checkpoints blockades (ICBs) therapy. We constructed a macrophage-related risk model through machine-learning, which might help us evaluate patients’ prognosis and response to ICBs therapy.

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Macrophages in Osteosarcoma Immune Microenvironment: Implications for Immunotherapy

Cited by 53 publications

References 143 publications

Extracellular Vesicles from Akkermansia muciniphila Elicit Antitumor Immunity Against Prostate Cancer via Modulation of CD8+ T Cells and Macrophages

Extracellular Vesicles from Akkermansia muciniphila Elicit Antitumor Immunity Against Prostate Cancer via Modulation of CD8+ T Cells and Macrophages

Expression of Lipid-Metabolism Genes Is Correlated With Immune Microenvironment and Predicts Prognosis in Osteosarcoma

The Heterogeneity of Infiltrating Macrophages in Metastatic Osteosarcoma and Its Correlation with Immunotherapy

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