scholarly journals STING Agonist Enhances the Efficacy of PD-L1 Monoclonal Antibody in Breast Cancer Immunotherapy by Activating the IFNβ Signaling Pathway

Author(s):  
Mingming Yin ◽  
Jinlong Hu ◽  
Zhongxu Yuan ◽  
Guangyi Luo ◽  
Jiaming Yao ◽  
...  

Abstract Purpose: This article focused on STING agonist role in breast cancer (BCa) immunotherapy.Methods: Clinical samples were collected from 37 BCa patients'. Xenograft tumor model was established by injecting 4T1 cells into mammary fat pad of mice. STING agonist and Atezolizumab were injected into mice with 2 times a week for 2 weeks. Peripheral blood, xenograft tumor, lung, liver, brain-cortex and kidney of mice were collected. Anti-IFNAR1 was used to treat 4T1 cells. Quantitative reverse transcription-polymerase chain reaction and Western blot were used for mRNA and proteins expression. Enzyme-linked immunosorbent assay, immunohistochemistry and hematoxylin-eosin staining were performed. Results: Tumor tissues of BCa patients exhibited lower STING and high PD-1 and PD-L1 protein expression. STING agonist inhibited 4T1 cells growth in mice (P < 0.001). STING agonist increased IFNβ level and the phosphorylation of STING, TBK1, IRF3 and STAT1 in xenograft tumor (P < 0.001). STING agonist synergized with Atezolizumab to inhibit 4T1 cells growth in mice, and increase TNF-α, IFN-β and IL-10 level in peripheral blood and xenograft tumor (P < 0.01). STING agonist synergized with Atezolizumab to increase CD8+ cytotoxic T cells and decrease FOXP3+ Tregs cells in xenograft tumor. STING agonist was non-toxic to lung, liver, brain-cortex and kidney. Anti-IFNAR1 reversed STING agonist promotion on TBK1, IRF3 and STAT1 phosphorylation in 4T1 cells (P < 0.01).Conclusion: STING agonist enhances the efficacy of Atezolizumab in BCa immunotherapy by activating the IFNβ signaling pathway.

2020 ◽  
Author(s):  
Jie Zhang ◽  
Lina Zhang ◽  
Jianlong Wang ◽  
Jing Zhao ◽  
Xuelian Zhao ◽  
...  

Abstract Background: Leucine zipper tumor suppressor 2 (LZTS2), an emerging tumor-suppressor, is attenuated in multiple cancers including prostate, lung and colon cancer. However, its expression and upstream regulatory mechanisms in triple negative breast cancer (TNBC) still remain unknown.Materials and methods: The expression of LZTS2 in TNBC and matched para-carcinoma tissues was detected with immunohistochemistry. The correlations between LZTS2 expression and clinicopathological parameters were analyzed. Kaplan-Meier analysis was performed to determine the prognostic role of LZTS2 for TNBC patients. CCK-8, wound healing and transwell assay were used to detect the effect of LZTS2 overexpression on the proliferation, migration and invasion ability, respectively. The bioinformation algorithms were used to reveal the potential upstream regulatory miRNA. Then, dual-luciferase reporter assay was performed to confirm the regulatory effect of the chosen miRNA on the expression of LZTS2. miR-9-5p inhibitor was used to determine the effect of miR-9-5p on the subcellular localization of β-catenin. Then, western blotting was performed to reveal the effect of miR-9-5p on EMT-related proteins in TNBC cells. Xenograft tumor model was established to reveal the effect of miR-9-5p on TNBC progression in vivo.Results: Low expression of LZTS2 was observed in 62 of 95 cases of TNBC tissue. Low expression of LZTS2 was correlated with poor postoperative DFS and OS of TNBC patients. LZTS2 could inhibit the proliferation, migration and invasion ability of TNBC cells. LZTS2 could be downregulated by miR-9-5p in TNBC, and the nuclear export of β-catenin was suppressed. Consequently, miR-9-5p inhibitor downregulated E-cadherin and upregulated N-cadherin, Twist and Vimentin in TNBC cells. Xenograft tumor model showed that miR-9-5p inhibitor could upregulate the expression of LZTS2 and induce nuclear export of β-catenin in TNBC.Conclusions: miR-9-5p contributes to β-catenin-activated EMT via downregulating LZTS2, and thus promotes TNBC progression.


2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Weiguang Liu ◽  
Jianjun Han ◽  
Sufang Shi ◽  
Yuna Dai ◽  
Jianchao He

Abstract Background Triple negative breast cancer (TNBC) is a breast cancer (BC) subtype that is characterized by its strong invasion and a high risk of metastasis. However, the specific mechanisms underlying these phenotypes are unclear. TUFT1 plays an important role in BC and impacts the proliferation and survival of BC cells. Recent studies have shown that TUFT1 mediates intracellular lysosome localization and vesicle transport by regulating Rab GTPase, but the relevance of this activity in TNBC is unknown. Therefore, our aim was to systematically study the role of TUFT1 in the metastasis and chemoresistance of TNBC. Methods We measured TUFT1, Rab5-GTP, and Rac1-GTP expression levels in samples of human TNBC by immunohistochemistry (IHC) and conducted univariate and multivariate analyses. shRNA-mediated knockdown and overexpression, combined with transwell assays, co-immunoprecipitation, a nude mouse xenograft tumor model, and GTP activity assays were used for further mechanistic studies. Results TUFT1 expression was positively correlated with Rab5-GTP and Rac1-GTP in the TNBC samples, and co-expression of TUFT1 and Rab5-GTP predicted poor prognosis in TNBC patients who were treated with chemotherapy. Mechanism studies showed that TUFT1 could activate Rab5 by binding to p85α, leading to activation of Rac1 through recruitment of Tiam1, and concurrent down-regulation of the NF-κB pathway and proapoptotic factors, ultimately promoting metastasis and chemoresistance in TNBC cells. Conclusions Our findings suggest that the TUFT1/Rab5/Rac1 pathway may be a potential target for the effective treatment of TNBC.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jiafeng Gao ◽  
Yi-Nan Zhang ◽  
Jingwen Cui ◽  
Jiatong Zhang ◽  
Yuexiang Ming ◽  
...  

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) that mediate T-cell immune responses. Breast cancer is one of the most commonly diagnosed diseases and its mortality rate is higher than any other cancer in both humans and canines. Plantain polysaccharide (PLP), extracted from the whole plant of Plantago asiatica L., could promote the maturation of DCs. In this research, we found that PLP could upregulate the maturation of DCs both in vitro and in vivo. PLP-activated DCs could stimulate lymphocytes’ proliferation and differentiate naive T cells into cytotoxic T cells. Tumor antigen-specific lymphocyte responses were enhanced by PLP and CIPp canine breast tumor cells lysate-pulsed DCs, and PLP and CIPp-cell-lysate jointly stimulated DCs cocultured with lymphocytes having the great cytotoxicity on CIPp cells. In the 4T1 murine breast tumor model, PLP could control the size of breast tumors and improve immunity by recruiting DCs, macrophages, and CD4+ and CD8+ T cells in the tumor microenvironment. These results indicated that PLP could achieve immunotherapeutic effects and improve immunity in the breast tumor model.


2020 ◽  
Vol 21 (3) ◽  
pp. 805 ◽  
Author(s):  
Shaolan Li ◽  
Yang Fan ◽  
Asako Kumagai ◽  
Emi Kawakita ◽  
Munehiro Kitada ◽  
...  

Dipeptidyl peptidase (DPP)-4, a molecular target of DPP-4 inhibitors, which are type 2 diabetes drugs, is expressed in a variety of cell types, tissues and organs. DPP-4 has been shown to be involved in cancer biology, and we have recently shown that a DPP-4 inhibitor promoted the epithelial mesenchymal transition (EMT) in breast cancer cells. The EMT is known to associate with chemotherapy resistance via the induction of ATP-binding cassette (ABC) transporters in cancer cells. Here, we demonstrated that deficiency in DPP-4 promoted chemotherapy resistance via the CXCL12/CXCR4/mTOR axis, activating the TGFβ signaling pathway via the expression of ABC transporters. DPP-4 inhibition enhanced ABC transporters in vivo and in vitro. Doxorubicin (DOX) further induced ABC transporters in DPP-4-deficient 4T1 cells, and the induction of ABC transporters was suppressed by either the CXCR4 inhibitor AMD3100, the mTOR inhibitor rapamycin or a neutralizing TGFβ (1, 2 and 3) antibody(N-TGFβ). Knockdown of snail, an EMT-inducible transcription factor, suppressed ABC transporter levels in DOX-treated DPP-4-deficient 4T1 cells. In an allograft mouse model, however, the effects of DOX in either primary tumor or metastasis were not statistically different between control and DPP-4-kd 4T1. Taken together, our findings suggest that DPP-4 inhibitors potentiate chemotherapy resistance via the induction of ABC transporters by the CXCL12/CXCR4/mTOR/TGFβ signaling pathway in breast cancer cells.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10026-10026
Author(s):  
T. Fujita ◽  
K. Kawasaki ◽  
D. Takabatake ◽  
H. Takahashi ◽  
Y. Ogasawara ◽  
...  

10026 Background: Trastuzumab is the only HER2/neu-directed therapy for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumor and the patient’s prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here we propose PTEN as a predictive biomarker for trastuzumab efficacy. Methods: Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were analyzed, in vitro. Also we examined, retrospectively, clinical samples from patients who had been treated with trastuzumab for the metastatic disease and analyzed the relationship between trastuzumab efficacy and PTEN expression profile with immunihistochemistry. The PTEN expression level was scored semiquantitatively based on staining intensity and distribution using the immunoreactive score. Statistical analysis was performed using the two-tailed student’s t test, Fisher’s test and ANOVA. Results: The PI3K/Akt signaling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was significanctly low compared with parental SKBR3 cells. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signaling pathway was also recognized in oligonucleotid delivered parental cells. Moreover, in clinical analysis, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in patients with elevated PTEN expression and statistically significant (p<0.05). Conclusions: PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated anti-tumor effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer. No significant financial relationships to disclose.


2019 ◽  
Vol 18 ◽  
pp. 153473541988025 ◽  
Author(s):  
Nurul Elyani Mohamad ◽  
Nadiah Abu ◽  
Swee Keong Yeap ◽  
Noorjahan Banu Alitheen

Background: This study aimed to evaluate the antitumor enhancing effect of bromelain consumption on 4T1-challenged mice treated with cisplatin. Methods: Mice challenged with 4T1 triple-negative breast cancer cells received water, bromelain, cisplatin, or bromelain + cisplatin treatment for 28 days. Tumor size was measured, and lung metastasis was evaluated by clonogenic assay. Expression of tumor inflammatory genes of the harvested tumor was quantified by polymerase chain reaction array and ELISA (enzyme-linked immunosorbent assay). Results: All treatments significantly reduced the size of tumor and lung metastasis, with combination treatment showing the best effect. Also, bromelain alone and combination treatment showed downregulation of the expression of tumor inflammatory genes (Gremlin [GREM1], interleukin 1β [IL-1β], interleukin-4 [IL-4], nuclear factor κB subunit 1 [NFκB1], and prostaglandin-endoperoxide synthase 2 [PTGS2]), tumor nitric oxide level, and serum IL-1β, and IL-4 levels. On the other hand, cisplatin treatment increased the expression of selected inflammatory markers. Conclusion: This study suggests that bromelain treatment could potentiate the antitumor effect of cisplatin on triple-negative breast cancer 4T1 cells through modulating the tumor environmental inflammation.


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