Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer

Shuai, Chong; Yang, Xinmei; Pan, Hongming; Han, Weidong

doi:10.3389/fonc.2020.582863

Cited by 50 publications

(38 citation statements)

References 46 publications

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“…Additionally, we studied the relationship between HIF1α, IL17A, and CXCL10 and immune microenvironment of BC. It is well known that TNBC and HER2+ BC are more tightly related to immune response ( Shuai et al, 2020 ), so we primarily analyzed the association of these three genes with several immune cell subsets (CD4+ T cell, CD8+ T cell, neutrophil, dendritic cell, and macrophage) in TNBC and HER2+ BC population. Among these immune cells, only infiltration of neutrophils was positively correlated with HIF1α, IL17A, and CXCL10 expression, while other types of immune cells were weakly related to these three genes ( Figures 6A–C ).…”

Section: Resultsmentioning

confidence: 99%

HIF1α Regulates IL17 Signaling Pathway Influencing Sensitivity of Taxane-Based Chemotherapy for Breast Cancer

Dai

Sheng

Wang

et al. 2021

Front. Cell Dev. Biol.

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Hypoxia-induced chemotherapy resistance is the main hindrance for solid tumor treatment. Hypoxia inducible factor-1α (HIF1α), an adaptive gene of hypoxia condition, played an important role in affecting chemotherapy sensitivity for many cancer types and various therapeutic regimens. This study focused on the impact of HIF1α on predicting response and survival of taxane-based neoadjuvant therapy (NAT) for breast cancer (BC) patients and the concrete mechanism that HIF1α mediated paclitaxel chemo-insensitivity. We evaluated HIF1α expression immunohistochemically from biopsies of 108 BC patients receiving paclitaxel–cisplatin NAT. Univariate and multivariate logistic regression analysis revealed that high HIF1α expression led to lower rate of pathological complete response (pCR) and worse prognosis. Analysis of GEO datasets also indicated negative association between HIF1α expression and response of taxane-based NAT in BC patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of differential expression genes (DEGs) in different HIF1α expression groups from TCGA database showed that HIF1α participated in interleukin 17 (IL-17) signaling pathway. Correlation analysis suggested that HIF1α was positively related to the IL-17 pathway. CXC motif chemokine ligand 10 (CXCL10) was the only DEG in the IL-17 pathway inversely relating to NAT response. Experiments in vitro verified that HIF1α/IL-17 pathway influences paclitaxel sensitivity to BC cells. Correlation analysis between HIF1α/IL-17A/CXCL10 and infiltration of immune cells in BC uncovered that high expression of all the above three genes were positively correlated to neutrophil infiltration in BC. Collectively, our findings shed novel insight into the mechanism of chemotherapy resistance and implied that HIF1α inhibitor may be a promising drug combined with traditional chemotherapeutic drug to increase the chemotherapy efficacy.

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Section: Resultsmentioning

confidence: 99%

HIF1α Regulates IL17 Signaling Pathway Influencing Sensitivity of Taxane-Based Chemotherapy for Breast Cancer

Dai

Sheng

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Consequently, it has been thought that the upregulation of PD-L1 in tumor cells (a rare phenomenon in BC) could be related to tumor immune evasion [61,111]. PD-L1 mRNA was found to be expressed in at least 20% of BC cells [112] and the majority of tumors that upregulated PD-L1 are HR− (52% vs. 48%) [112,113]. Many studies have relatively consistently reported that PD-L1 represents a good survival prognostic factor in TNBC [114][115][116][117][118][119], whereas the clinical role of PD-L1 is not clear in HR+ patients [61].…”

Section: Highlights Of Pd1/pd-l1 and Hr+ Bcmentioning

confidence: 99%

Luminal Breast Cancer: Risk of Recurrence and Tumor-Associated Immune Suppression

Pellegrino

Hlavatá²,

Migali

et al. 2021

Mol Diagn Ther

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Hormone-receptor positive (HR+) breast cancer (BC) (including the luminal A and the luminal B subtypes) is the most common type of tumor in women diagnosed with early-stage BC (EBC). It represents a highly heterogeneous subgroup that is characterized by different risks of relapse. The aim of this review is to discuss the possible role played by the immune response in predicting this risk, along with the most common clinical and pathological factors and molecular tools that have been developed and are already in use. As opposed to what has previously been observed in the most aggressive human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC) subtypes, a high proportion of tumor-infiltrating lymphocytes (TILs)-reflecting a spontaneous and pre-existing immune response to the tumor-has been linked to a worse prognosis in HR+ EBC. This work provides some immune biological rationale explaining these findings and provides the basics to understand the principal clinical trials that are testing immunotherapy in HR+ (luminal) BC.Antonino Musolino and Cinzia Solinas contributed equally to this work.

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“…IL-17E acted as an antagonist of IL-17 pathway by suppressing the activation function of IL-17A, IL-17C, and IL-17F. The inhibition of ER-induced IL-17 signaling decreases the expression level of PD-L1 in ER + breast cancer, which reveals the essential role of IL-17 in ER-induced PD-L1 expression decrease [ 64 ].…”

Section: Cancer Cellmentioning

confidence: 99%

Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment

Wang¹,

Jin

Qian

et al. 2021

Cancer Cell Int

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As the essential sexual hormone, estrogen and its receptor has been proved to participate in the regulation of autoimmunity diseases and anti-tumor immunity. The adjustment of tumor immunity is related to the interaction between cancer cells, immune cells and tumor microenvironment, all of which is considered as the potential target in estrogen-induced immune system regulation. However, the specific mechanism of estrogen-induced immunity is poorly understood. Typically, estrogen causes the nuclear localization of estrogen/estrogen receptor complex and alternates the transcription pattern of target genes, leading to the reprogramming of tumor cells and differentiation of immune cells. However, the estrogen-induced non-canonical signal pathway activation is also crucial to the rapid function of estrogen, such as NF-κB, MAPK-ERK, and β-catenin pathway activation, which has not been totally illuminated. So, the investigation of estrogen modulatory mechanisms in these two manners is vital for the tumor immunity and can provide the potential for endocrine hormone targeted cancer immunotherapy. Here, this review summarized the estrogen-induced canonical and non-canonical signal transduction pathway and aimed to focus on the relationship among estrogen and cancer immunity as well as immune-related tumor microenvironment regulation. Results from these preclinical researches elucidated that the estrogen-target therapy has the application prospect of cancer immunotherapy, which requires the further translational research of these treatment strategies.

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Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer

Cited by 50 publications

References 46 publications

HIF1α Regulates IL17 Signaling Pathway Influencing Sensitivity of Taxane-Based Chemotherapy for Breast Cancer

HIF1α Regulates IL17 Signaling Pathway Influencing Sensitivity of Taxane-Based Chemotherapy for Breast Cancer

Luminal Breast Cancer: Risk of Recurrence and Tumor-Associated Immune Suppression

Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment

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