scholarly journals Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248996
Author(s):  
Gao Sheng ◽  
Hongyan Yuan ◽  
Lu Jin ◽  
Suman Ranjit ◽  
Julia Panov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Tumor Progression ◽  
Immune Tolerance ◽  
Cancer Survival ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Inflammatory Factors ◽  
Immune Tolerant

One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent immune surveillance. One such element associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poor survival. Fibrosis is caused by inflammatory factors and remodeling of the extracellular matrix that elicit an immune tolerant microenvironment. To address the role of fibrosis in tumorigenesis, we developed NeuT/ATTAC transgenic mice expressing a constitutively active NeuT/erbB2 transgene, and an inducible, fat-directed caspase-8 fusion protein, which upon activation results in selective and partial ablation of mammary fat and its replacement with fibrotic tissue. Induction of fibrosis in NeuT/ATTAC mice led to more rapid tumor development and an inflammatory and fibrotic stromal environment. In an effort to explore therapeutic options that could reduce fibrosis and immune tolerance, mice were treated with the oxysterol liver X receptor (LXR) pan agonist, N,N-dimethyl-3-β-hydroxy-cholenamide (DMHCA), an agent known to reduce fibrosis in non-malignant diseases. DMHCA reduced tumor progression, tumor multiplicity and fibrosis, and improved immune surveillance by reducing infiltrating myeloid-derived suppressor cells and increasing CD4 and CD8 effector T cells. These effects were associated with downregulation of an LXR-dependent gene network related to reduced breast cancer survival that included Spp1, S100a9, Anxa1, Mfge8 and Cd14. These findings suggest that the use of DMHCA may be a potentially effective approach to reduce desmoplasia and immune tolerance and increase the efficacy of cancer therapy.

Utilizing Cancer - Functional Gene Set - Compound Networks to Identify Putative Drugs for Breast Cancer

2018 ◽  
Vol 21 (2) ◽  
pp. 74-83
Author(s):  
Tzu-Hung Hsiao ◽  
Yu-Chiao Chiu ◽  
Yu-Heng Chen ◽  
Yu-Ching Hsu ◽  
Hung-I Harry Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Cancer Survival ◽  
Expression Profiles ◽  
Functional Gene ◽  
Gene Set Enrichment Analysis ◽  
Gene Set ◽  
Gene Sets

Aim and Objective: The number of anticancer drugs available currently is limited, and some of them have low treatment response rates. Moreover, developing a new drug for cancer therapy is labor intensive and sometimes cost prohibitive. Therefore, “repositioning” of known cancer treatment compounds can speed up the development time and potentially increase the response rate of cancer therapy. This study proposes a systems biology method for identifying new compound candidates for cancer treatment in two separate procedures. Materials and Methods: First, a “gene set–compound” network was constructed by conducting gene set enrichment analysis on the expression profile of responses to a compound. Second, survival analyses were applied to gene expression profiles derived from four breast cancer patient cohorts to identify gene sets that are associated with cancer survival. A “cancer–functional gene set– compound” network was constructed, and candidate anticancer compounds were identified. Through the use of breast cancer as an example, 162 breast cancer survival-associated gene sets and 172 putative compounds were obtained. Results: We demonstrated how to utilize the clinical relevance of previous studies through gene sets and then connect it to candidate compounds by using gene expression data from the Connectivity Map. Specifically, we chose a gene set derived from a stem cell study to demonstrate its association with breast cancer prognosis and discussed six new compounds that can increase the expression of the gene set after the treatment. Conclusion: Our method can effectively identify compounds with a potential to be “repositioned” for cancer treatment according to their active mechanisms and their association with patients’ survival time.

Breaking immune tolerance for the treatment of glioblastoma: Phase IIb clinical trial experience.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 71-71
Author(s):  
Larn Hwang ◽  
David Nam ◽  
Vuong N. Trieu
Keyword(s):  
Immune Tolerance ◽  
Tumor Vaccine ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Test Group ◽  
High Grade Glioma ◽  
Dose Finding ◽  
Control Group ◽  
Open Label ◽  
The Individual

71 Background: Intratumoral heterogeneity (IH) resulting in the temporal and spatial diversification of tumor subclones. IH occurs progressively during tumor development inherent to the individual predilection to mutation and in the face of counterselections by exogenous therapies and/or endogenous immune surveillance. The xenogenization is countered by immunosuppression via overexpression of TGF-β. Here we compare the use of temozolomide (TMZ) and OT-101/TMZ to break immune tolerance to glioblastoma (GBM) for the cure. OT-101 is an antisense against TGF-β2. Methods: This is a phase IIb, multi-national, multi-center, open-label, active-controlled, randomized parallel group dose-finding study to evaluate the efficacy and safety of OT-101 in adult patients with recurrent high-grade glioma, administered intratumorally as continuous high-flow microperfusion over a 7-day period every other week. A total of 134 patients, 89 patients in the OT-101 test group and 45 patients in the standard chemotherapy (TMZ) control group were assessed. Results: Multiple rounds of TMZ broke the immune tolerance as shown by increase in overall survival (OS). mOS increased from 5.6 mos, 7.9 mos, to 36.6 mos with 1 round, 2 rounds, and 3 rounds of TMZ, respectively (p<0.0001). For OT-101, mOS increased from 4.6 mos to 21.6 mos with just one round of TMZ (p<0.0001) reducing the negative side effects of TMZ. Treatment sequencing was important as lead-in OT101 followed with subsequent TMZ was more effective than TMZ prior to OT-101 (26.2 mos vs. 4.8 mos, p<0.0001). Conclusions: The MOA for OT-101/TMZ is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during TMZ. Contrary to traditional tumor vaccine- this is universally applicable to all patients.

scholarly journals The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

2008 ◽  
Vol 25 (4) ◽  
pp. 357-369 ◽  
Author(s):  
Nigel P. S. Crawford ◽  
Renard C. Walker ◽  
Luanne Lukes ◽  
Jennifer S. Officewala ◽  
Robert W. Williams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Cancer Survival ◽  
Breast Cancer Survival ◽  
Transcriptional Network

scholarly journals Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer

2020 ◽  
Vol 3 (11) ◽  
pp. e202000893
Author(s):  
Meliha Mehmeti-Ajradini ◽  
Caroline Bergenfelz ◽  
Anna-Maria Larsson ◽  
Robert Carlsson ◽  
Kristian Riesbeck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Immune Cell ◽  
Human Tumor ◽  
Metastatic Breast ◽  
Suppressor Cells ◽  
Breast Cancer Patients ◽  
Maturation Stages

Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.

scholarly journals Heterogeneous Myeloid Cells in Tumors

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3772
Author(s):  
Aixia Dou ◽  
Jing Fang
Keyword(s):  
Cancer Therapy ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Clonal Evolution ◽  
Critical Role ◽  
Tumor Development ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Main Function ◽  
Opposing Effects

Accumulating studies highlight a critical role of myeloid cells in cancer biology and therapy. The myeloid cells constitute the major components of tumor microenvironment (TME). The most studied tumor-associated myeloid cells (TAMCs) include monocytes, tumor-associated macrophages (TAMs), dendritic cells (DCs), cancer-related circulating neutrophils, tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). These heterogenous myeloid cells perform pro-tumor or anti-tumor function, exerting complex and even opposing effects on all stages of tumor development, such as malignant clonal evolution, growth, survival, invasiveness, dissemination and metastasis of tumor cells. TAMCs also reshape TME and tumor vasculature to favor tumor development. The main function of these myeloid cells is to modulate the behavior of lymphocytes, forming immunostimulatory or immunosuppressive TME cues. In addition, TAMCs play a critical role in modulating the response to cancer therapy. Targeting TAMCs is vigorously tested as monotherapy or in combination with chemotherapy or immunotherapy. This review briefly introduces the TAMC subpopulations and their function in tumor cells, TME, angiogenesis, immunomodulation, and cancer therapy.

scholarly journals Transforming Growth Factor-Beta1 and Myeloid-Derived Suppressor Cells Interplay in Cancer

2017 ◽  
Vol 6 (1) ◽  
pp. 1-14
Author(s):  
Juan F. Santibanez ◽  
Suncica Bjelica
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

Background: Transforming growth factor-beta1 (TGF-β1) is a pleiotropic cytokine with a double role in cancer through its capacity to inhibit early stages of tumors while enhancing tumor progression at late stages of tumor progression. Moreover, TGF-β1 is a potent immunosuppressive cytokine within the tumor microenvironment that allows cancer cells to escape from immune surveillance, which largely contributes to the tumor progression. Method: It has been established that the cancer progression is commonly associated with increased number of Myeloid-derived suppressor cells (MDSC) that are a hallmark of cancer and a key mechanism of immune evasion. Result: MDSC represent a population of heterogeneous myeloid cells comprised of macrophages, granulocytes and dendritic cells at immature stages of development. MDSC promote tumor progression by regulating immune responses as well as tumor angiogenesis and cancer metastasis. Conclusion: In this review, we present an overview of the main key functions of both TGF-β1 and MDSC in cancer and in the immune system. Furthermore, the mutual contribution between TGF-β1 and MDSC in the regulation of immune system and cancer development will be analyzed.

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