The Distinct Roles of CXCR3 Variants and Their Ligands in the Tumor Microenvironment

Reynders, Nathan; Abboud, Dayana; Baragli, Alessandra; Noman, Muhammad Zaeem; Rogister, Bernard; Niclou, Simone P.; Heveker, Nikolaus; Janji, Bassam; Hanson, Julien; Szpakowska, Martyna; Chevigné, Andy

doi:10.3390/cells8060613

Cited by 67 publications

(62 citation statements)

References 139 publications

(174 reference statements)

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“…In our study, the PPI plot of common DEGs shared by stromal and immune signatures also showed that various cytokines, especially chemokine and chemokine receptor family including CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CCL13, CCL19, CCL21, CCR1, CCR2, CCR5, CCR7, CXCR3, and CXCR4, were the most active and quite important cytokines in TME. Some of these chemokines and receptors, such as CXCL13, CCL4, CCL5, CCR2, CXCR3, and CXCR4, have been experimentally confirmed to be associated with the pathogenesis or prognosis of gastric cancer or other malignancies [39,[40][41][42][43]. In our study, CXCL9, CXCL10, and CXCL11 were found to be overexpressed in STAD compared with the normal control and in the stromal signature.…”

supporting

confidence: 59%

“…The common receptor of these ligands was CXCR3, which had three spliced variants in human (CXCR3A, CXCR3B, and CXCR3-alt). CXCR3 is usually expressed on the surface of tumor cells, monocytes, dendritic cells, T cells, and NK cells [42]. CXCL9, CXCL 10, and CXCL11 were reported to recruit immune cells to TME, stimulate and induce immune cells such as macrophages, CD8+ T cells, and NK cells to produce TNF-α, IFN-γ, and IL-2 through Th1 polarization and activation, and thus enhance antitumor immunity.…”

mentioning

confidence: 99%

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Potential Prognostic Value and Mechanism of Stromal-Immune Signature in Tumor Microenvironment for Stomach Adenocarcinoma

Zhu

Xie

Zhao

et al. 2020

BioMed Research International

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Stomach adenocarcinoma (STAD) is one of the most common malignancies. But the molecular mechanism is unknown. In this study, we downloaded the transcriptional profiles and clinical data of 344 STAD and 30 normal samples from The Cancer Genome Atlas (TCGA) database. Stromal and immune scores of STAD were calculated by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm, and association of stromal/immune scores with tumor differentiation/T/N/M stage and survival was investigated. The differentially expressed genes (DEGs) between high and low score groups (based on media) were identified, and prognostic genes over-/underexpressed in both STAD and stromal/immune signature were retrieved. Furthermore, proportions of 22 infiltrating immune cells for the cohort from TCGA were estimated by the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) algorithm, and association of 22 immune cells with tumor differentiation/T/N/M stage and survival was investigated. Next, coexpression analysis of 22 immune cells and intersection genes over-/underexpressed in both STAD and stromal signature was conducted. We found high stromal and immune scores and macrophage infiltration predicting poor tumor differentiation and severe local invasion, obtained a list of prognostic genes based on stromal-immune signature, and explored the interaction of collagen, chemokines such as CXCL9, CXCL10, and CXCL11, and macrophage through coexpression analysis and may provide novel prognostic biomarkers and immunotherapeutic targets for STAD.

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supporting

confidence: 59%

mentioning

confidence: 99%

Potential Prognostic Value and Mechanism of Stromal-Immune Signature in Tumor Microenvironment for Stomach Adenocarcinoma

Zhu

Xie

Zhao

et al. 2020

BioMed Research International

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“…Although it was shown that the expression of CXCR3 on T lymphocytes mediates their migration to the tumor side, the presence of CXCR3 on malignant cells promoted tumor growth and dissemination. Notably, two isoforms of CXCR3 with opposite effects might be present in the TME [65]. Our results are consistent with recent meta-analyses, which have shown that higher CXCR3 expression indicates an advanced tumor stage and is correlated with the occurrence of distant metastasis in solid tumors [66,67].…”

Section: Discussionsupporting

confidence: 92%

The Expression of Selected Factors Related to T Lymphocyte Activity in Canine Mammary Tumors

Bujak

Szopa

Pingwara

et al. 2020

IJMS

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Crosstalk between neoplastic and immune cells in the tumor microenvironment (TME) influences the progression of disease in human and canine cancer patients. Given that canine mammary tumors are a useful model to study breast cancer biology, we aimed to evaluate the expression of genes associated with T lymphocyte activity in benign, malignant, and metastatic canine mammary tumors. Interestingly, metastatic tumors exhibit increased expression of CXCR3, CCR2, IL-4, IL-12p40, and IL-17. In particular, we focused on IL-17, a key interleukin associated with the Th17 lymphocyte phenotype. Th17 cells have been shown to play a contradictory role in tumor immunity. Although IL-17 showed a high expression in the metastatic tumors, the expression of RORγt, a crucial transcription factor for Th17 differentiation was barely detected. We further investigated IL-17 expression using immunohistochemistry, through which we confirmed the increased expression of this interleukin in malignant and metastatic mammary tumors. Finally, we compared the plasma levels of IL-17 in healthy and malignant mammary tumor-bearing dogs using ELISA but found no differences between the groups. Our data indicate that the IL-17 in metastatic tumors may be produced by other cell types, but not by Th17 lymphocytes. Overall, our results broaden the available knowledge on the interactions in canine mammary tumors and provide insight into the development of new therapeutic strategies, with potential benefits for human immune oncology.

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“…The role of CXCL9–CXCR3 signaling in immune cell activation and migration in development and pathological processes has been well documented ( 43 – 45 ). It has, however, also been shown that CXCR3 acts independently of CXCL9, via CXCL4, CXCL10, or CXCL11 ( 46 – 48 ).…”

Section: Discussionmentioning

confidence: 99%

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model

Phan

Tan

Liu

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only a few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify druggable pathways, we generated a medaka (Oryzias latipes) osteoporosis model, where inducible expression of receptor-activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts and excessive bone resorption, which can be assessed by live imaging. Here we show that upon Rankl induction, osteoblast progenitors up-regulate expression of the chemokine ligand Cxcl9l. Ectopic expression of Cxcl9l recruits mpeg1-positive macrophages to bone matrix and triggers their differentiation into osteoclasts. We also demonstrate that the chemokine receptor Cxcr3.2 is expressed in a distinct subset of macrophages in the aorta-gonad-mesonephros (AGM). Live imaging revealed that upon Rankl induction, Cxcr3.2-positive macrophages get activated, migrate to bone matrix, and differentiate into osteoclasts. Importantly, mutations in cxcr3.2 prevent macrophage recruitment and osteoclast differentiation. Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis.

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The Distinct Roles of CXCR3 Variants and Their Ligands in the Tumor Microenvironment

Cited by 67 publications

References 139 publications

Potential Prognostic Value and Mechanism of Stromal-Immune Signature in Tumor Microenvironment for Stomach Adenocarcinoma

Potential Prognostic Value and Mechanism of Stromal-Immune Signature in Tumor Microenvironment for Stomach Adenocarcinoma

The Expression of Selected Factors Related to T Lymphocyte Activity in Canine Mammary Tumors

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model

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