Local production of the chemokines CCL5 and CXCL10 attracts CD8+ T lymphocytes into esophageal squamous cell carcinoma

Liu, Jinyan; Li, Feng; Yü, Ping; Wang, Liping; Chen, Xinfeng; Wang, Dan; Cao, Liu; Zhao, Song; Li, Bing; Kaliński, Paweł; Thorne, Stephen H.; Zhang, Bin; Zhang, Yi

doi:10.18632/oncotarget.4617

Cited by 93 publications

(81 citation statements)

References 44 publications

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“…Further, knockdown of CCL5 in murine colorectal carcinoma cells delays tumor growth and decreases both Treg cell infiltration and CD8 ϩ T-cell apoptosis (65). In contrast, in human ESCC tissue samples, CCL5 is correlated with increased CD8 ϩ lymphocyte markers and a prolonged overall survival of patients (66). In this study, 4-MU decreased the Ccl5 mRNA expression in CAF co-cultures.…”

Section: Journal Of Biological Chemistry 4101mentioning

confidence: 51%

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Kretschmer

Freudenberger

Twarock

et al. 2016

Journal of Biological Chemistry

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The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less ␣-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4 ؉ but not CD8 ؉ cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response.

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Section: Journal Of Biological Chemistry 4101mentioning

confidence: 51%

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Kretschmer

Freudenberger

Twarock

et al. 2016

Journal of Biological Chemistry

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“…Nevertheless, 5-aza-induced local production of cytokines, including CCL5 (Fig. 3), which are known to attract T cells (53,54), suggests possibly beneficial, at least for some patients, combination of 5-aza with immunotherapy (anti-PD-L1/PD-1), as the number of tumor-infiltrating CD8 þ T cells was found to predict response to anti-PD-1/PD-L1…”

Section: -Azamentioning

confidence: 99%

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Biktasova

Hajek

Sewell

et al. 2017

Clinical Cancer Research

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Purpose: DNA methylation in human papillomavirus-associated (HPV þ ) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV þ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV þ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV þ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV þ HNSCC. classically associated with tobacco and alcohol exposure, including loss-of-function mutations of TP53 (84%) and loss or inactivating mutations of CDKN2A (54%). In contrast, genetic alterations in these genes are extremely rare in the HPV þ subset (TP53, 3%; CDKN2A, 0%; ref. 6), which instead is associated with a mutational signature typical of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) antiviral proteins (6, 11-13). In addition, The Cancer Genome Atlas (TCGA) head and neck study found that TNF receptor-associated factor 3 (TRAF3) and CYLD genes are commonly mutated and deleted in HPV þ HNSCC (6,8,14). Finally, HPV À HNSCC have relatively low levels of DNA methylation, which is correlated with genomic instability (15), whereas HPV þ HNSCC harbor distinctly hypermethylated genomes (7,8,16,17). Demographic, clinical, molecular, and epigenetic differences between HPV þ and HPV À HNSCC suggest two distinct cancers, yet HPV À status is currently only used for prognosis and not to guide treatment (18). A majority of HNSCC patients are treated with radiation and platin-based chemotherapy, which is associated with deleterious and lifelong side-effects. Despite the relatively good prognosis associated with HPV þ HNSCC, 25%-30% of patients with HPV-positive tumors experience recurrent or metastatic disease, for which treatment options are limited. The molecular and epigenetic differences between HPV þ and HPV À tumors provide an opportunity for therapies that exploit the interaction of the HPV genome and host that result in hypermethylation of cancer cell genomes. 5-Azacytidine (5-aza)

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“…Relatively recent studies have revealed that chemokines regulate the movement of a wide variety of immune cells including lymphocytes, NK cells, and DCs in both physiological and pathological conditions (79). These features mean that chemokines play crucial roles in immune responses.…”

Section: The Important Role Of Chemokines In Lung Carcinomamentioning

confidence: 99%

The paradoxical role of tumor-infiltrating immune cells in lung cancer

Zheng

Yao

2017

IRDR

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Local production of the chemokines CCL5 and CXCL10 attracts CD8+ T lymphocytes into esophageal squamous cell carcinoma

Cited by 93 publications

References 44 publications

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

The paradoxical role of tumor-infiltrating immune cells in lung cancer

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