Tim3/Gal9 interactions between T cells and monocytes result in an immunosuppressive feedback loop that inhibits Th1 responses in osteosarcoma patients

Li, Xiuzhong; Chen, Yanqing; Xu, Liang; Zhang, Jin; Xu, He; Teng, Guangju; Yu, Dazhi

doi:10.1016/j.intimp.2017.01.006

Cited by 40 publications

(33 citation statements)

References 22 publications

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“…To further confirm the effect of Gal-9 on the cells, we added carrier-free recombinant Gal-9 (R&D Systems, Inc., Minneapolis, MN, USA) into the medium (19). After 24 h, the results showed that IL-6 and TNF-α were dosage-dependently decreased, whereas IL-10 and TGF-β were significantly increased with increasing levels of rGal-9 (0.1-1 µg/ml) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of M1-type and M2-type macrophage polarization in RAW264.7 cells by Galectin-9

Bao

2017

Molecular Medicine Reports

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Generally considered as a potent pro‑inflammatory signal, β‑galactosidelectin suppresses T cell receptor activation, can both promote and inhibit integrin‑mediated adhesion and is required in nuclear pre‑mRNA splicing. Galectin‑9 (Gal‑9), a member of β‑galactoside lectin, is involved many processes of T cell‑mediated diseases (such as autoimmune diseases and asthma) and immunomodulation of macrophages. Macrophages are involved in the occurrence of inflammation, development and digestion and other stages. At different stages of the inflammatory response, macrophages exhibit different phenotypes, but mainly two subtypes, classically (M1) or alternatively (M2) polarization. The purpose of this work is to investigate the effect of overexpression or knockdown of Gal‑9 on the macrophage polarization. Macrophage polarization was detected by flow cytometric profiling of secreted cytokines and specific surface markers expression, including nitric oxide synthase 2 (NOS2) and mannose receptor 1 (CD206). Protein and mRNA expression levels of TNF‑α, TGF‑β, IL‑6, IL‑10, NF‑κB, signal transducer and activator of transcription (Stat)1 and Stat3 were determined by ELISA, western blot analysis or qRT‑PCR. Our results implied that differentiation of the mouse macrophage line RAW264.7 into M1‑type and M2‑type macrophages is followed by marked variations of Gal‑9 expression. Furthermore, its overexpression and secretion are tightly associated with M2‑type macrophages, whereas its downregulation promotes macrophages to polarize into M1‑type macrophages, which confirmed by elevated CD206 and NOS2, respectively. In response to the changes of Gal‑9 expression, cytokines, transcription factors and regulators, including TNF‑α, IL‑6, NF‑κB, Stat1, TGF‑β, IL‑10, and Stat3, were tightly regulated and significantly associated with classically and alternatively activated macrophages. Consistent with characteristics of M1‑type macrophages, the transcriptional or translational expression levels or activity of TNF‑α, IL‑6, Stat1 and NF‑κB were markedly increased with knockdown of Gal‑9 in macrophages. By contrast, the expression levels or activity of TGF‑β, IL‑10 and Stat3 were clearly elevated in macrophages with Gal‑9 overexpression, which is closely related with M2‑type macrophages. Specific expression and secretion patterns of cytokines, transcription factors and regulators in M1‑type and M2‑type macrophages contribute to better understanding the role of Gal‑9 in regulation in macrophages. This study provides a new insight that Gal‑9 may be a new immunomodulatory target for macrophages.

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Section: Resultsmentioning

confidence: 99%

Regulation of M1-type and M2-type macrophage polarization in RAW264.7 cells by Galectin-9

Bao

2017

Molecular Medicine Reports

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“…[67]. Tim3/Gal9 interactions between T cells and myeloid cells could also result in an immunosuppressive response and repressed inflammation [68].…”

Section: Osteosarcoma Cells Modulate the Balance Between Pro-and Antimentioning

confidence: 99%

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

Heymann

Lezot

Heymann

2019

Cellular Immunology

171

183

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“…Complementing the participatory role of TAMs, several studies have focused on characterizing tumor infiltrating lymphocytes (TILs) and their contribution to metastasis immunobiology. Analyses of TILs within the OS microenvironment have shown that both effector and suppressor T lymphocyte (CD3 + ) phenotypes participate in shaping immunosurveillance of OS lesions (229,230,(234)(235)(236). Furthermore, several studies suggest that the density (number) or phenotype (activated or exhausted) of effector TILs within OS primary tumors correlate with prognosis.…”

Section: Leveraging the Immune System To Combat Os Metastasesmentioning

confidence: 99%

“…Provocatively, the functional relevance of TILs and operative checkpoint blockade mechanisms might be especially important for metastases, as some studies have found the density of TILs to be enriched in metastatic lesions compared to primary tumors (236,237). Despite the presence of TILs within OS lesions, several studies suggest that the activity of effector TILs might be attenuated, as supported by the expression of exhaustion markers (PD-1, CTLA-4, Tim3) by TILs and/or tumoral microenvironmental expression of PD-L1 (227)(228)(229)(235)(236)(237). Collectively, these detailed studies strongly suggest that OS lesions can be effectively infiltrated by T lymphocytes, and that therapeutic modulation of checkpoint blockade strategies could improve TILs effector capabilities.…”

Section: Leveraging the Immune System To Combat Os Metastasesmentioning

confidence: 99%

Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

2020

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Osteosarcoma is a malignant primary tumor of bone, arising from transformed progenitor cells with osteoblastic differentiation and osteoid production. While categorized as a rare tumor, most patients diagnosed with osteosarcoma are adolescents in their second decade of life and underscores the potential for life changing consequences in this vulnerable population. In the setting of localized disease, conventional treatment for osteosarcoma affords a cure rate approaching 70%; however, survival for patients suffering from metastatic disease remain disappointing with only 20% of individuals being alive past 5 years post-diagnosis. In patients with incurable disease, pulmonary metastases remain the leading cause for osteosarcoma-associated mortality; yet identifying new strategies for combating metastatic progression remains at a scientific and clinical impasse, with no significant advancements for the past four decades. While there is resonating clinical urgency for newer and more effective treatment options for managing osteosarcoma metastases, the discovery of druggable targets and development of innovative therapies for inhibiting metastatic progression will require a deeper and more detailed understanding of osteosarcoma metastasis biology. Toward the goal of illuminating the processes involved in cancer metastasis, a convergent science approach inclusive of diverse disciplines spanning the biology and physical science domains can offer novel and synergistic perspectives, inventive, and sophisticated model systems, and disruptive experimental approaches that can accelerate the discovery and characterization of key processes operative during metastatic progression. Through the lens of trans-disciplinary research, the field of comparative oncology is uniquely positioned to advance new discoveries in metastasis biology toward impactful clinical translation through the inclusion of pet dogs diagnosed with metastatic osteosarcoma. Given the spontaneous course of osteosarcoma development in the context of real-time tumor microenvironmental cues and immune mechanisms, pet dogs are distinctively valuable in translational modeling given their faithful recapitulation of metastatic disease

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Tim3/Gal9 interactions between T cells and monocytes result in an immunosuppressive feedback loop that inhibits Th1 responses in osteosarcoma patients

Cited by 40 publications

References 22 publications

Regulation of M1-type and M2-type macrophage polarization in RAW264.7 cells by Galectin-9

Regulation of M1-type and M2-type macrophage polarization in RAW264.7 cells by Galectin-9

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

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