Biological role of GITR/GITRL in attributes and immune responses of macrophage

Zhuo, Fu; Wang, Shuang; Li, Jinhua; Zhang, Yunfeng; Liang, Han; Li, Guangquan; Wan, Xue

doi:10.1002/jlb.3a0919-387rr

Cited by 10 publications

(10 citation statements)

References 51 publications

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“…This polarization of M2 toward M1-like macrophages is consistent with previous report in a pancreatic tumor model with low-dose radiation (30). We previously observed a peak of GITRL + macrophage on the first day after irradiation (data not shown), which is a marker of M1 macrophage (31). This peak typically resolved as Tregs were upregulated in the tumor.…”

Section: Discussionsupporting

confidence: 92%

Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma

Kohno

Murakami

et al. 2020

The Journal of Immunology

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Increasing evidence indicates that local hypofractionated radiotherapy (LRT) can elicit both immunogenic and immunosuppressive local and systemic immune responses. We thus hypothesized that blockade of LRT-induced immunosuppressive responses could augment the antitumor effects and induce an abscopal response. In this study, we found that the upregulation of Foxp3 + regulatory T cells (Tregs) in the mesothelioma tumor microenvironment after nonablative oligofractionated irradiation significantly limited the success of irradiation. Using DEREG mice, which allow conditional and efficient depletion of Foxp3 + Tregs by diphtheria toxin injection, we observed that transient Foxp3 + Treg depletion immediately after nonablative oligofractionated irradiation provided synergistic local control and biased the T cell repertoire toward central and effector memory T cells, resulting in long-term cure. Furthermore, this combination therapy showed significant abscopal effect on the nonirradiated tumors in a concomitant model of mesothelioma through systemic activation of cytotoxic T cells and enhanced production of IFN-g and granzyme B. Although local control was preserved with one fraction of nonablative irradiation, three fractions were required to generate the abscopal effect. PD-1 and CTLA-4 were upregulated on tumor-infiltrating CD4 + and CD8 + T cells in irradiated and nonirradiated tumors, suggesting that immune checkpoint inhibitors could be beneficial after LRT and Foxp3 + Treg depletion. Our findings are applicable to the strategy of immuno-radiotherapy for generating optimal antitumor immune responses in the clinical setting. Targeting Tregs immediately after a short course of irradiation could have a major impact on the local response to irradiation and its abscopal effect.

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Section: Discussionsupporting

confidence: 92%

Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma

Kohno

Murakami

et al. 2020

The Journal of Immunology

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“…We found that the fibrogenic factor TGF-β1 could induce hepatic progenitor cells to express GITRL, hepatic progenitor cells are another cell compartment expressing GITRL in chronic HBV-induced cirrhotic human liver tissue, and high GITRL expression correlates with disease severity and poor clinical outcome of HCC. Our overexpression and silencing data support the growth stimulatory effect of GITRL on hepatic progenitor cells, which is similar to the effect of GITRL on macrophages [ 38 ]. As a cell compartment involved in HCC carcinogenesis [ 8 , 9 ], hepatic progenitor cells expressing GITRL activate pathways of cancer, MAPK, PI3K/Akt and epithelial–mesenchymal transition by binding to ANXA2, which could enhance the progression of HCC [ 39 – 41 ] and many other tumours, including colorectal cancer [ 42 ], pancreatic cancer [ 43 ], breast cancer [ 44 , 45 ] and prostate cancer [ 46 ], suggesting that GITRL may contribute to the abnormal transformation of hepatic progenitor cells.…”

Section: Discussionsupporting

confidence: 83%

GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt

Pei

et al. 2022

Cell Death Dis

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Hepatic stem/progenitor cells are the major cell compartment for tissue repair when hepatocyte proliferation is compromised in chronic liver diseases, but the expansion of these cells increases the risk of carcinogenesis. Therefore, it is essential to explore the pathways restricting their expansion and abnormal transformation. The ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL) showed the most highly increased expression in hepatic progenitor cells treated with transforming growth factor (TGF)-β1. If overexpressed by hepatic progenitor cells, GITRL stimulated cell proliferation by activating the epithelial–mesenchymal transition pathway and enhancing ERK1/2 and Akt phosphorylation via GITRL binding to ANXA2. However, GITR, the specific GITRL receptor, suppressed the epithelial–mesenchymal transition pathway of GITRL-expressing cells and decreased their growth by dissociating ANXA2 from GITRL and reducing downstream ERK1/2 and Akt phosphorylation. This study identifies GITR/GITRL reverse signalling as a cross-interaction pathway between immune cells and hepatic stem/progenitor cells that restricts the expansion of hepatic stem/progenitor cells and reduces the possibility of carcinogenesis.

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“…GITRL is an activating immune checkpoint ligand that binds to the GITR receptor. These immune modulators are key players in autoimmune diseases and in the immune responses of macrophages [ 51 , 52 ]. In our study, GITRL was significantly upregulated in OSCC tissue compared to NOM.…”

Section: Discussionmentioning

confidence: 99%

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Weber

Lutz

Olmos

et al. 2022

Cancers

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Background: The involvement of immune cell infiltration and immune regulation in the progression of oral squamous cell carcinoma (OSCC) is shown. Anti-PD-1 therapy is approved for the treatment of advanced OSCC cases, but not all patients respond to immune checkpoint inhibitors. Hence, further targets for therapeutic approaches are needed. The number of identified cellular receptors with immune checkpoint function is constantly increasing. This study aimed to perform a comparative analysis of a large number of immune checkpoints in OSCC in order to identify possible targets for therapeutic application. Materials and Methods: A NanoString mRNA analysis was performed to assess the expression levels of 21 immune regulatory checkpoint molecules in OSCC tissue (n = 98) and healthy oral mucosa (NOM; n = 41). The expression rates were compared between the two groups, and their association with prognostic parameters was determined. Additionally, relevant correlations between the expression levels of different checkpoints were examined. Results: In OSCC tissue, significantly increased expression of CD115, CD163, CD68, CD86, CD96, GITRL, CD28 and PD-L1 was detected. Additionally, a marginally significant increase in CD8 expression was observed. BTLA and PD-1 levels were substantially increased, but the differential expression was not statistically significant. The expression of CD137L was significantly downregulated in OSCC compared to NOM. Correlations between immune checkpoint expression levels were demonstrated, and some occurred specifically in OSCC tissue. Conclusions: The upregulation of inhibitory receptors and ligands and the downregulation of activators could contribute to reduced effector T-cell function and could induce local immunosuppression in OSCC. Increased expression of activating actors of the immune system could be explained by the increased infiltration of myeloid cells and T-cells in OSCC tissue. The analysis contributes to the understanding of immune escape in OSCC and reveals potential targets for oral cancer immunotherapy.

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Biological role of GITR/GITRL in attributes and immune responses of macrophage

Cited by 10 publications

References 51 publications

Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma

Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma

GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

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