scholarly journals Icariin‐induced inhibition of SIRT6/NF‐κB triggers redox mediated apoptosis and enhances anti‐tumor immunity in triple‐negative breast cancer

2020 ◽  
Vol 111 (11) ◽  
pp. 4242-4256
Author(s):  
Linjiang Song ◽  
Xian Chen ◽  
Ling Mi ◽  
Chi Liu ◽  
Shaomi Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Immunity ◽  
Triple Negative Breast Cancer ◽  
Triple Negative

scholarly journals Cry1Ac Protoxin Confers Antitumor Adjuvant Effect in a Triple-Negative Breast Cancer Mouse Model by Improving Tumor Immunity

2022 ◽  
Vol 16 ◽  
pp. 117822342110651
Author(s):  
Servin-Garrido Roberto Raúl ◽  
Ilhuicatzi-Alvarado Damaris ◽  
Jiménez-Chávez Ángel de Jesús ◽  
Moreno-Fierros Leticia
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Tumor Immunity ◽  
Triple Negative Breast Cancer ◽  
Cellular Response ◽  
Triple Negative ◽  
Vehicle Group ◽  
Cytotoxic T Cell ◽  
Adjuvant Effect ◽  
Cry1ac Toxin

The Cry1Ac protoxin from Bacillus thuringiensis is a systemic and mucosal adjuvant, able to confer protective immunity in different infection murine models and induce both Th1 and TCD8+ cytotoxic lymphocyte responses, which are required to induce antitumor immunity. The Cry1Ac toxin, despite having not being characterized as an adjuvant, has also proved to be immunogenic and able to activate macrophages. Here, we investigated the potential antitumor adjuvant effect conferred by the Cry1Ac protoxin and Cry1Ac toxin in a triple negative breast cancer (TNBC) murine model. First, we evaluated the ability of Cry1Ac proteins to improve dendritic cell (DC) activation and cellular response through intraperitoneal (i.p.) coadministration with the 4T1 cellular lysate. Mice coadministered with the Cry1Ac protoxin showed an increase in the number and activation of CD11c+MHCII- and CD11c+MHCII+low in the peritoneal cavity and an increase in DC activation (CD11c+MHCII+) in the spleen. Cry1Ac protoxin increased the proliferation of TCD4+ and TCD8+ lymphocytes in the spleen and mesenteric lymph nodes (MLN), while the Cry1Ac toxin only increased the proliferation of TCD4+ and TCD8+ in the MLN. Remarkably, when tested in the in vivo TNBC mouse model, prophylactic immunizations with 4T1 lysates plus the Cry1Ac protoxin protected mice from developing tumors. The antitumor effect conferred by the Cry1Ac protoxin also increased specific cytotoxic T cell responses, and prevented the typical tumor-related decrease of T cells (TCD3+ and TCD4+) as well the increase of myeloid-derived suppressor cells (MDSC) in spleen. Also in the tumor microenvironment of mice coadministered twice with Cry1Ac protoxin immunological improvements were found such as reductions in immunosupressive populations (T regulatory lymphocytes and MDSC) along with increases in macrophages upregulating CD86. These results show a differential antitumor adjuvant capability of Cry1Ac proteins, highlighting the ability of Cry1Ac protoxin to enhance local and systemic tumor immunity in TNBC. Finally, using a therapeutic approach, we evaluated the coadministration of Cry1Ac protoxin with doxorubicin. A significant reduction in tumor volume and lung metastasis was found, with increased intratumoral levels of tumor necrosis factor-α and IL-6 with respect to the vehicle group, further supporting its antitumor applicability.

scholarly journals TGF-β inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity

Theranostics ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 1910-1922 ◽  
Author(s):  
Myrofora Panagi ◽  
Chrysovalantis Voutouri ◽  
Fotios Mpekris ◽  
Panagiotis Papageorgis ◽  
Margaret R Martin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Immunity ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Microenvironment

Abstract 1955: Investigating anti-tumor immunity with CDK4/6 inhibition in triple negative breast cancer

2021 ◽  
Author(s):  
Qiuchen Guo ◽  
Milos Spasic ◽  
Gregory Goreczny ◽  
Adam Maynard ◽  
Sandra McAllister
Keyword(s):  
Breast Cancer ◽  
Tumor Immunity ◽  
Triple Negative Breast Cancer ◽  
Triple Negative

scholarly journals 845 A colony stimulating factor 1 receptor-blocking bifunctional protein simultaneously targets tumor-associated macrophages and exhausted T cells for the treatment of triple-negative breast cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A886-A886
Author(s):  
Pandelakis Koni ◽  
Hung-Kai Chen ◽  
Yao-Wen Chang ◽  
Huey-Wen Hsiao ◽  
Chih-Lun Hsiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Fusion Protein ◽  
Tumor Immunity ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Model ◽  
Colony Stimulating Factor ◽  
Stimulating Factor

BackgroundTumor-associated macrophages (TAMs) are a significantly-poor prognostic factor for patients with triple-negative breast cancer (TNBC). The tumor microenvironment of TNBC features highly-infiltrating TAMs that contribute to tumor progression and metastasis. Therefore, TAM-targeted immunotherapies are recognized as a potential approach for treating TNBC. However, depleting TAMs alone by use of monoclonal antibodies against colony-stimulating factor 1 receptor (CSF1R) was insufficient to cause substantial tumor control. Recent studies revealed that interleukin-10 (IL-10) can directly activate terminally-exhausted CD8+ T cells to boost anti-tumor activity. We set forth to investigate whether a combination of anti-CSF1R antibody with a half-life-extended IL-10-Fc fusion protein (IL-10-Fc) may enhance anti-tumor immunity, and whether synergistic effects could be achieved with bifunctional antibody forms.MethodsAntibodies and recombinant proteins were produced in-house. In vitro CSF1R activity was evaluated by Western blot analysis of CSF1-mediated CSF1R phosphorylation and monocyte proliferation assays. In vitro IL10 activity was evaluated by MC/9 cell proliferation and CD8 T cell activation assays. 4T1 mouse breast tumor studies were performed at the National Yang Ming Chiao Tung University (Taiwan). Other tumor model studies employed the services of Crownbio (China). Methods of RNAseq analysis of 4T1 tumor masses included Cibersort, gene set enrichment analysis (GSEA) and immune gene signature score analysis.ResultsCo-treatment with a recombinant human IL-10-Fc protein significantly improved the anti-tumor efficacy of anti-mouse CSF1R antibody in a mouse CT26 colon tumor model. It was then hypothesized that a better synergistic effect could be achieved by a bifunctional anti-mouse CSF1R-IL-10 fusion protein (anti-mCSF1R-IL-10), to allow targeted-delivery of IL-10 to CSF1R-positive-TAM-rich tumor microenvironments. Indeed, anti-mCSF1R-IL-10 showed greatly increased anti-tumor efficacy in both EMT-6 and 4T1 mouse models of breast cancer. Consistent with the in vivo efficacy, gene expression profiling revealed an enhanced intratumoral interferon-gamma signature by treatment with anti-mCSF1R-IL-10 as compared to either anti-mCSF1R or IL-10-Fc alone. An anti-human CSF1R-IL-10 (hCSF1R-IL-10) was also constructed using a newly-produced anti-human CSF1R antibody and tested in cell-based functional assays, demonstrating that anti-hCSF1R-IL-10 could both inhibit CSF1-dependent cell growth and activate tumor-infiltrating T cells isolated from tumor biopsies of triple-negative breast cancer patients. Further validation of this bifunctional form will be presented.ConclusionsOur findings provide a potential strategy for simultaneously targeting TAM and exhausted T cells to potentiate anti-tumor immunity for treatment of triple-negative breast cancer.Ethics ApprovalThe studies were approved by the institutional animal care and use committee of National Yang Ming Chiao Tung University; approval numbers 1081025 and 109060.

Identification of new therapeutic leads for triple negative breast cancer subtypes

Planta Medica ◽  
2015 ◽  
Vol 81 (11) ◽  
Author(s):  
AJ Robles ◽  
L Du ◽  
S Cai ◽  
RH Cichewicz ◽  
SL Mooberry
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtypes ◽  
Cancer Subtypes ◽  
Therapeutic Leads
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