Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients

Bhat, Shreyas; Gardi, Nilesh; Hake, Sujata; Kotian, Nirupama; Sawant, Sharada; Kannan, Sadhana; Parmar, Vani; Desai, Sangeeta; Dutt, Amit; Joshi, Neha

doi:10.1007/s00432-017-2431-5

Cited by 17 publications

(10 citation statements)

References 60 publications

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“…Bhat et al (10) reported that the overall expression level of IL-17A in breast cancer is very low. It was also noticed in our study that transcripts encoding IL-17A and IL-17F in the majority of samples and transcripts encoding IL-17C and IL-17E in half of the samples were absent according to TCGA Breast Cancer dataset, which made the quantitative analysis difficult.…”

Section: Er Status Is Associated With the Expression Of Il-17 Family mentioning

confidence: 99%

“…A study of the correlation between the IL-17A level and clinicopathological parameters in patients with breast cancer showed that the number of IL-17A-producing cells in breast cancer tissue is related to a higher histological grade and negative ER/PR status but shows no relationship with tumor stage, tumor size, lymph node status, HER2 status, or histological type (9). Bhat et al (10) showed that IL-17A expression is increased in ER-negative breast cancer, and increased IL-17A levels are associated with the increased expression of T cell response genes.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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Background: The relationship between the interleukin 17 (IL-17) family of cytokines and breast cancer has been widely studied in recent years. Many studies have revealed increased levels of the cytokine IL-17A in estrogen receptor (ER)-negative or triple-negative breast cancer. Upregulation of IL-17A signaling is associated with increased expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in breast cancer with low ER expression and may elevate the infiltration of CD8 + T cells in tumor tissue. This study aims to determine whether ER downregulates the expression of PD-1/PD-L1, reduces the infiltration of CD8 + T cells, and affects the immune microenvironment by decreasing T-helper 17 (Th17) cell infiltration and inhibiting IL-17 signaling in breast cancer. Methods: Samples in The Cancer Genome Atlas Breast Cancer dataset were grouped by ER status and the PAM50 intrinsic subtype. The expression of IL-17 family cytokines and Th17 cell signature cytokines were compared between groups. IL-17 signaling pathway-related genes that were differentially expressed according to the ER level were identified. The PD-1 and PD-L1 levels were compared between breast cancer samples with different ER statuses and IL-17A/IL-17F expression levels. Correlation analyses of the expression of PD-1/PD-L1 and IL-17 signaling pathway-related genes were performed. The associations of the expression of IL-17 signaling pathway-related genes with the immune microenvironment were investigated. Results: High levels of ER decreased the expression of IL-17A, IL-17C, and IL-17F but increased the expression of IL-17E (IL25), which acts as a suppressor of IL-17 signaling. The expression levels of Th17 cell signature cytokines were significantly increased in ER-negative breast cancer. The expression levels of genes encoding downstream products of IL-17A/IL-17F signaling were downregulated in breast cancer with high ER expression. Increased expression of PD-1/PD-L1 was associated with ER-negative status, IL-17A-positive status, IL-17F-positive status, and upregulation of IL-17 signaling pathway-related genes in breast cancer. Enhanced IL-17 signal transduction was Shuai et al. Effect of ER in BC associated with the elevation of CD8 + T cell infiltration and variation of the immune microenvironment of breast cancer. Conclusion: High estrogen receptor levels decrease PD-1/PD-L1 expression and CD8 + T cell infiltration by suppressing Th17 cell infiltration and IL-17 signal transduction in breast cancer.

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Section: Er Status Is Associated With the Expression Of Il-17 Family mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Interestingly, in the present study we found that TAM-derived TNFα induced IL-32 expression in TC cells and IL-32 expression in tumour cells is known to affect adaptive immune responses in several other solid cancers [9]. In vitro studies and animal models of different solid cancer types, including colon and prostate cancer, have revealed that IL-32β can stimulate the adaptive anti-tumour response by inducing NK cytotoxicity, thereby increasing T cell infiltration and stimulating a cytotoxic T cell response [12,31,32]. As this was beyond the scope of our study, future studies are warranted to assess the effect of IL-32 on adaptive anti-tumour responses in TC.…”

Section: Discussionmentioning

confidence: 54%

Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

et al. 2019

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Purpose Interleukin 32 (IL-32) is a pro-inflammatory cytokine of which different isoforms have been identified. Recently, IL-32 has been shown to act as a potent inducer of cell migration in several types of cancer. Although previous research showed that IL-32 is expressed in differentiated thyroid cancer (TC) cells, the role of IL-32 in TC cell migration has not been investigated. Furthermore, tumour-associated macrophages (TAMs) may play a facilitating role in cancer cell migration. The aim of this study was to explore whether the interaction between TC cells and TAMs results in increased expression of IL-32 in TC cells and to investigate whether this affects TC cell migration. Methods TPC-1 cells were co-culture with TC-induced or naive macrophages. Next, transcriptome analysis on TPC-1 cells was performed and supernatants were used for stimulation of TPC-1 cells. IL-32β and IL-32γ were exogenously overexpressed in TPC-1 cells using transient transfection, after which an in vitro gap closure assay was performed to assess cell migration, and the expression of migratory factors was assessed using RT-qPCR. Results We found that TC-induced macrophages induced IL-32 expression in TC cells and that TAM-derived TNFα was the main inducer of IL-32β expression in TC cells. Overexpression of IL-32β and IL-32γ did not affect TC cell migration, but increased cell death. Finally, we found that IL-32β overexpression led to increased mRNA expression of the pro-survival cytokine IL-8, while the expression of other migratory factors was not affected. Conclusions From our data, we conclude that TAM-derived TNFα induces IL-32β in TC cells. Although IL-32β does not affect TC cell migration, alternative splicing of IL-32 towards the IL-32β isoform may be beneficial for TC cell survival through induction of the pro-survival cytokine IL-8.

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“…IL-17A-transfected murine fibrosarcoma cells, but not control tumor cells, have shown to induce tumor-specific CD4 and CD8 T cell responses to protect mice from secondary tumor challenge 21 . In addition, breast cancer patients with high intra-tumoral IL-17A expression have been shown to have strong intra-tumoral Th1 responses 28 . Finally, consistent with a previous study in which IL-17A was shown to increase tumor immunogenicity and immune activation in the TDLNs by promoting DC recruitment 23 , we observed an increased CD8α + DC population in the TDLNs of AdIL-17A-transduced tumors (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…IL-17A has been reported to have both pro-tumor 10 , 14 – 20 and anti-tumor effects 21 – 23 in murine tumor models. Similarly, some clinical studies have found that an enhanced IL-17/Th17 immune profile is associated with increased tumor invasiveness 24 – 27 , while others have correlated IL-17/Th17 responses with enhanced patient survival 28 , 29 . Many factors, such as the tumor type, the tumor stage, and the cellular source and kinetics of IL-17/Th17 responses, may contribute to the controversy in a context-dependent manner 6 , 30 – 32 .…”

Section: Introductionmentioning

confidence: 92%

Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas

Dawod

Liu

Gebremeskel

et al. 2020

Sci Rep

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Triple-negative breast cancer (TNBC) is an invasive subtype of breast cancer but paradoxically associated with increased tumor-infiltrating leukocytes. The molecular and cellular mechanisms underlying TNBC immunobiology are incompletely understood. Interleukin (IL)-17A is a pro-inflammatory cytokine that has both pro- and anti-tumor effects and found in 40–80% of TNBC samples. We report here that IL-17A mRNA and protein are detectable in some human TNBC cell lines and further upregulated by IL-23 and LPS stimulation. Furthermore, the impact of tumor-derived IL-17A in host immune response and tumor growth was examined using murine TNBC 4T1 mammary carcinoma cells transduced with an adenoviral vector expressing IL-17A (AdIL-17A) or control vector (Addl). Compared to Addl-transduction, AdIL-17A-transduction enhanced 4T1 tumor growth and lung metastasis in vivo, which was associated with a marked expansion of myeloid-derived suppressor cells (MDSCs). However, AdIL-17A-transduction also induced strong organ-specific and time-dependent immune activation indicated by dynamic changes of NK cells, B cells, CD4, and CD8 T cells in peripheral blood, lung, and tumor site, as well as the plasma levels of IFNγ. Such findings highlight that tumor-associated IL-17A induces concurrent immune activation and immune suppression. Administration of anti-Gr1 or anti-G-CSF antibody effectively depleted MDSCs in vivo, markedly reducing the growth of AdIL-17A-transduced 4T1 tumors, and eliminating lung metastasis. Collectively, our study demonstrates that MDSC depletion is an effective and practical approach for treating IL-17A-enriched mammary carcinomas.

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Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients

Cited by 17 publications

References 60 publications

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

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

Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas

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