CXCL14 Attenuates Triple-Negative Breast Cancer Progression by Regulating Immune Profiles of the Tumor Microenvironment in a T Cell-Dependent Manner

Gibbs, Carla; So, Jae Young; Ahad, Abdul; Son, Deok‐Soo; Li, Yang

doi:10.3390/ijms23169314

Cited by 4 publications

(3 citation statements)

References 44 publications

(44 reference statements)

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“…Indeed, CXCL14 has been reported to participate in mediating immune profiles in breast cancer, glioma, and sarcoma. 21,41,42 In glioma, CXCL14 promoted directional migration and chemotaxis of activated CD8+ T cells in a dose-dependent way in vitro. In vivo, CXCL14 was associated with prolonged survival in a CD8+ T-cell-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

CXCL14 as a potential marker for immunotherapy response prediction in renal cell carcinoma

Pan,

Liu,

Zhang

et al. 2023

Ther Adv Med Oncol

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Background: Epigenetic mechanisms play vital roles in the activation, differentiation, and effector function of immune cells. The breast and kidney-expressed chemokine (CXCL14) mainly contributes to the regulation of immune cells. However, its role in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in renal cell carcinoma (RCC). Objectives: This study aimed to elucidate the role of CXCL14 in predicting the efficacy of immunotherapy in patients with RCC. Methods: CXCL14 expression and RNA-sequencing, single-cell RNA-sequencing (scRNA-seq), and survival datasets of RCC from public databases were analyzed, and survival was compared between different CXCL14 levels. The correlation between CXCL14 and immune infiltration and human leukocyte antigen (HLA) gene expression was analyzed with TIMER2.0 and gene expression profiling interactive analysis. Institutional scRNA-seq and immunohistochemical staining analyses were used to verify the relationship between CXCL14 expression level and the efficacy of immunotherapy. Results: CXCL14 was expressed in fibroblast and malignant cells in RCC, and higher expression was associated with better survival. Enrichment analysis revealed that CXCL14 is involved in immune activation, primarily in antigen procession, antigen presentation, and major histocompatibility complex assemble. CXCL14 expression was positively correlated with T-cell infiltration as well as HLA-related gene expression. Among the RCC cohort receiving nivolumab in Checkmate 025, the patients with CXCL14 high expression had better overall survival than those with CXCL14 low expression after immunotherapy. scRNA-seq revealed a cluster of CXCL14+ fibroblast in immunotherapy responders. Immunohistochemistry analysis verified that the patients with high CXCL14 expression had an increased proportion of high CD8 expression simultaneously. The expression level of CXCL14 was associated with CXCR4 expression in RCC. Conclusion: CXCL14 expression is associated with immunotherapy response in RCC. It is a promising biomarker for immunotherapy response prediction and may be an effective epigenetic modulator in combination with immunotherapy approaches.

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Section: Discussionmentioning

confidence: 99%

CXCL14 as a potential marker for immunotherapy response prediction in renal cell carcinoma

Pan,

Liu,

Zhang

et al. 2023

Ther Adv Med Oncol

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“…Increasing the proportion of M1-type macrophages is an important indicator of good prognosis in cancer [14,15]. Although CXCL14 is a relatively novel gene in the chemokine family, it has long been reported that CXCL14 is closely related to the occurrence of breast cancer, liver cancer, lung cancer and other cancers [16][17][18][19][20][21][22]. It has been found that CXCL14 is significantly downregulated in HPV-positive head/neck cancer and cervical tissue specimens, and restoring the expression of CXCL14 in oropharyngeal cancer cells could clear tumors in mice [23].…”

Section: Discussionmentioning

confidence: 99%

Yak-Derived CXCL14 Activates the Pro-Inflammatory Response of Macrophages and Inhibits the Proliferation and Migration of HepG2

Li,

Wang

et al. 2023

Animals

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CXCL14 (C-X-C motif chemokine ligand 14) is an important chemokine involved in infection and immunity and plays an important role in a variety of immune-related diseases. The 446 bp cDNA sequence of the CXCL14 gene in yaks was obtained. Additionally, the prokaryotic expression vector of the CXCL14 protein with a molecular weight of 27 kDa was successfully constructed and expressed. The proliferation activities and migration abilities of spleen macrophages were significantly inhibited after treatment with the CXCL14 protein at different concentrations (1, 10 and 20 μg/mL) (p < 0.05). Furthermore, the expressions of pro-inflammatory cytokines interleukin 1 beta (IL-1β), interleukin 6 (IL6), interleukin 8 (IL8) and interferon-α (TNF-α) were significantly increased (p < 0.05), but the expression of anti-inflammatory factor interleukin 10 (IL10) was significantly decreased (p < 0.05). The contents of inflammatory factors in the supernatant of cells were detected using ELISA, and it was also found that the contents of TNF-α, IL6 and cytochrome c oxidase subunit II (COX2) were significantly increased under different CXCL14 protein concentrations (p < 0.05). Finally, the exogenous addition of CXCL14 inhibited the activity, clonal formation and migration of hepatoma cells (HepG2). Additionally, after HepG2 cells were treated with 20 μg/mL CXCL14 protein for 12 h, 24 h and 36 h, the expression levels of BCL2 homologous antagonist/killer (BAK) and the BCL2-associated X apoptosis regulator (BAX) were increased to varying degrees, while the expression levels of hypoxia-inducible factor 1 subunit alpha (HIF1A), the mechanistic target of rapamycin kinase (mTOR) and cyclin-dependent kinase 1 (CDK1) genes decreased compared to the control group. In conclusion, the CXCL14 protein can inhibit the proliferation and migration of HepG2 cells by inducing the expression of macrophage pro-inflammatory factors and activating apoptosis-related genes to exert innate immunity. These results are helpful to further study the function of the CXCL14 protein and provide research data for the innate immune mechanism of yaks under harsh plateau environments.

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“…Furthermore, the aggressive TNBC phenotype has been associated with epigenetic modulation, calcium signaling, and the loss of MHC I [ 9 , 10 , 11 ]. Currently, attenuation of TNBC progression by modulating the cancer signaling pathways such as by inhibiting CDK14, induction of chemokines such as CXCL14, and inhibition of NF-κB is promising [ 12 , 13 , 14 ]. The NF-κB pathway is highly associated with BC, as shown by its inhibition via parthenolide that inhibits TNBC progression, inducing apoptosis in mammary tumors, enhancing chemo-sensitivity in BC cells, and suppressing metastatic markers in TNBC [ 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer

et al. 2023

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Breast cancer (BC) is the most common cancer type among women with a distinct clinical presentation, but the survival rate remains moderate despite advances in multimodal therapy. Consequently, a deeper understanding of the molecular etiology is required for the development of more effective treatments for BC. The relationship between inflammation and tumorigenesis is well established, and the activation of the pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is frequently identified in BC. Constitutive NF-κB activation is linked to cell survival, metastasis, proliferation, and hormonal, chemo-, and radiotherapy resistance. Moreover, the crosstalk between NF-κB and other transcription factors is well documented. It is reported that vitamin C plays a key role in preventing and treating a number of pathological conditions, including cancer, when administered at remarkably high doses. Indeed, vitamin C can regulate the activation of NF-κB by inhibiting specific NF-κB-dependent genes and multiple stimuli. In this review, we examine the various NF-κB impacts on BC development. We also provide some insight into how the NF-κB network may be targeted as a potential vulnerability by using natural pro-oxidant therapies such as vitamin C.

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CXCL14 Attenuates Triple-Negative Breast Cancer Progression by Regulating Immune Profiles of the Tumor Microenvironment in a T Cell-Dependent Manner

Cited by 4 publications

References 44 publications

CXCL14 as a potential marker for immunotherapy response prediction in renal cell carcinoma

CXCL14 as a potential marker for immunotherapy response prediction in renal cell carcinoma

Yak-Derived CXCL14 Activates the Pro-Inflammatory Response of Macrophages and Inhibits the Proliferation and Migration of HepG2

The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer

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