Vesicular IFN-γ as a cooperative attacker to enhance anti-cancer effect of 5-fluorouracil via thymidine phosphorylase upregulation and tumor microenvironment normalization

2021 ◽  
pp. 102501
Author(s):  
Yan Peng ◽  
Yumiao Hu ◽  
Liyan Qiu
Keyword(s):  
Tumor Microenvironment ◽  
Thymidine Phosphorylase ◽  
Anti Cancer ◽  
Ifn Γ

scholarly journals A Palette of Cytokines to Measure Anti-Tumor Efficacy of T Cell-Based Therapeutics

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 821
Author(s):  
Prathyaya Ramesh ◽  
Rohan Shivde ◽  
Dinesh Jaishankar ◽  
Diana Saleiro ◽  
I. Caroline Le Poole
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Mechanisms Of Action ◽  
Immune Monitoring ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Ifn Γ

Cytokines are key molecules within the tumor microenvironment (TME) that can be used as biomarkers to predict the magnitude of anti-tumor immune responses. During immune monitoring, it has been customary to predict outcomes based on the abundance of a single cytokine, in particular IFN-γ or TGF-β, as a readout of ongoing anti-cancer immunity. However, individual cytokines within the TME can exhibit dual opposing roles. For example, both IFN-γ and TGF-β have been associated with pro- and anti-tumor functions. Moreover, cytokines originating from different cellular sources influence the crosstalk between CD4+ and CD8+ T cells, while the array of cytokines expressed by T cells is also instrumental in defining the mechanisms of action and efficacy of treatments. Thus, it becomes increasingly clear that a reliable readout of ongoing immunity within the TME will have to include more than the measurement of a single cytokine. This review focuses on defining a panel of cytokines that could help to reliably predict and analyze the outcomes of T cell-based anti-tumor therapies.

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

Antitumor effects of Auraptene in 4T1 tumor‐bearing Balb/c mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mohammad Reza. Shiran ◽  
Davar Amani ◽  
Abolghasem Ajami ◽  
Mahshad Jalalpourroodsari ◽  
Maghsoud Khalizadeh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Body Weight ◽  
Tumor Volume ◽  
Serum Levels ◽  
Ki 67 ◽  
Tumor Bearing ◽  
Paraffin Oil ◽  
Anti Cancer ◽  
Before And After ◽  
Ifn Γ

Abstract Objectives Breast cancer is a common malignant tumor in women with limited treatment options and multiple side effects. Today, the anti-cancer properties of natural compounds have attracted widespread attention from researchers worldwide. Methods In this study, we treated 4T1 tumor-bearing Balb/c mice with intraperitoneal injection of Auraptene, paraffin oil, and saline as two control groups. Body weight and tumor volume were measured before and after treatment. Hematoxylin and eosin (H & E) staining and immunohistochemistry of Ki-67 were used as markers of proliferation. In addition, ELISA assays were performed to assess serum IFN-γ and IL-4 levels. Results There was no significant change in body weight in all animal groups before and after treatment. 10 days after the last treatment, Auraptene showed its anti-cancer effect, which was confirmed by the smaller tumor volume and H & E staining. In addition, Ki-67 expression levels were significantly reduced in tumor samples from the Auraptene-treated group compared to the paraffin oil and saline-treated groups. In addition, in tumor-bearing and normal mice receiving Auraptene treatment, IL-4 serum production levels were reduced, while serum levels of IFN-γ were significantly up-regulated in tumor-bearing mice after Auraptene treatment. Conclusions In the case of inhibition of tumor volume and Ki-67 proliferation markers, Auraptene can effectively inhibit tumor growth in breast cancer animal models. In addition, it might increases Th1 and CD8 + T cell responses after reducing IL-4 serum levels and IFN-γ upregulation, respectively. However, further research is needed to clarify its mechanism of action.

Abstract 1384: Selective PI3Kγ inhibitor ZX-4081 reprograms the tumor microenvironment to facilitate anti-cancer immunity

2021 ◽  
Author(s):  
Ying-Ying Li ◽  
Kun Guo ◽  
Zhiyuan Peng ◽  
Deming Kong ◽  
Xiaolin Hao ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunity ◽  
Anti Cancer

scholarly journals Semaphorin Signaling in Cancer-Associated Inflammation

2019 ◽  
Vol 20 (2) ◽  
pp. 377 ◽  
Author(s):  
Giulia Franzolin ◽  
Luca Tamagnone
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Disease Progression ◽  
Tumor Cells ◽  
Cross Talk ◽  
Immune Cells ◽  
Major Element ◽  
Inflammatory Cells ◽  
Anti Cancer

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment.

scholarly journals Exosome-transmitted miR-769-5p confers cisplatin resistance and tumorigenesis in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53

2021 ◽  
Author(s):  
Xinming Jing ◽  
Mengyan Xie ◽  
Kun Ding ◽  
Tingting Xu ◽  
Yuan Fang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Microenvironment ◽  
Cisplatin Resistance ◽  
Biologically Active ◽  
Clinical Prognosis ◽  
Anti Cancer ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
New Treatment ◽  
Apoptosis Related Protein

AbstractCisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism of cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participates in tumor metastasis and drug resistance. In this study, we discovered that cisplatin-resistant GC cells communicate with the tumor microenvironment by secreting microvesicles. The biologically active miR-769-5p can be integrated into exosomes and delivered to sensitive cells, thereby spreading cisplatin resistance. Mi769-5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin-resistant patients. Mechanistically, miR-769-5p promotes cisplatin resistance by targeting CASP9 so as to inhibit the downstream caspase pathway and promote the degradation of the apoptosis-related protein p53 through the ubiquitin-proteasome pathway. Targeting miR-769 with its antagonist to treat cisplatin-resistant GC cells can restore the cisplatin response, confirming that exosomal miR-769-5p can be a key regulator of cisplatin resistance in GC. Therefore, exosomal miR-769-5p derived from drug-resistant cells can be used as a potential therapeutic predictor of anti-tumor chemotherapy to enhance the effect of anti-cancer chemotherapy, which provides a new treatment option for GC.

Psoralidin exerts anti-tumor, anti-angiogenic, and immunostimulatory activities in 4T1 tumor‐bearing balb/c mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Davar Amani ◽  
Elham Shakiba ◽  
Ehsan Motaghi ◽  
Hiva Alipanah ◽  
Mahshad Jalalpourroodsari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Body Weight ◽  
Serum Level ◽  
Tumor Volume ◽  
Treated Group ◽  
The Body ◽  
Ki 67 ◽  
Tumor Bearing ◽  
Anti Cancer ◽  
Ifn Γ

Abstract Background Psoralidin as a compound of the Psoralea corylifolia seeds exhibited several anti-cancer potentials in various cancers. Materials and methods In this study, 4T1 tumor‐bearing Balb/c mice were treated by intraperitoneal administration of Psoralidin, and Paraffin, as a control group to investigate anti-tumor, anti-angiogenic, and immunostimulatory activities in breast cancer. Body weight and tumor volume measurement were performed. Hematoxylin and Eosin (H&E) staining as well as immunohistochemistry for Ki-67, CD31 and VEGF markers were conducted. In addition, ELISA assay was performed for evaluating the serum level of IFN-γ and IL-4. Moreover, real time assay was performed to evaluate the expression of angiogenesis and immunostimulatory related genes. Results There were no significant changes in the body weight of all animal groups. The anti-cancer effects of Psoralidin were significantly observed after 24 days of the last treatment, confirmed by smaller tumor volume and also H&E staining. The expression level of Ki‐67, CD31 and VEGF were significantly decreased in tumor tissues of the Psoralidin-treated group in comparison with Paraffin-treated group. Moreover, there was a significant reduction in the serum level of IL-4 in tumor-bearing mice after Psoralidin treatment while the serum level of IFN-γ was significantly augmented in all groups. Moreover, the reduction in expression of VEGF-a and IL-1β was observed. Interestingly Psoralidin treatment led to expression increase of FOXp3. Conclusions Psoralidin shows the anti-cancer potential in an animal model of breast cancer; however, further studies are recommended to elucidate its mechanisms of action.

scholarly journals Tumor Microenvironment as A “Game Changer” in Cancer Radiotherapy

2019 ◽  
Vol 20 (13) ◽  
pp. 3212 ◽  
Author(s):  
Magdalena Jarosz-Biej ◽  
Ryszard Smolarczyk ◽  
Tomasz Cichoń ◽  
Natalia Kułach
Keyword(s):  
Immune System ◽  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Tumor Hypoxia ◽  
Suppressor Cells ◽  
Anticancer Efficacy ◽  
Anti Cancer ◽  
Radiation Induced ◽  
Game Changer

Radiotherapy (RT), besides cancer cells, also affects the tumor microenvironment (TME): tumor blood vessels and cells of the immune system. It damages endothelial cells and causes radiation-induced inflammation. Damaged vessels inhibit the infiltration of CD8+ T lymphocytes into tumors, and immunosuppressive pathways are activated. They lead to the accumulation of radioresistant suppressor cells, including tumor-associated macrophages (TAMs) with the M2 phenotype, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). The area of tumor hypoxia increases. Hypoxia reduces oxygen-dependent DNA damage and weakens the anti-cancer RT effect. It activates the formation of new blood vessels and leads to cancer relapse after irradiation. Irradiation may also activate the immune response through immunogenic cell death induction. This leads to the “in situ” vaccination effect. In this article, we review how changes in the TME affect radiation-induced anticancer efficacy. There is a very delicate balance between the activation of the immune system and the immunosuppression induced by RT. The effects of RT doses on immune system reactions and also on tumor vascularization remain unclear. A better understanding of these interactions will contribute to the optimization of RT treatment, which may prevent the recurrence of cancer.

scholarly journals Microfluidic modelling of the tumor microenvironment for anti-cancer drug development

Lab on a Chip ◽  
2019 ◽  
Vol 19 (3) ◽  
pp. 369-386 ◽  
Author(s):  
Menglin Shang ◽  
Ren Hao Soon ◽  
Chwee Teck Lim ◽  
Bee Luan Khoo ◽  
Jongyoon Han
Keyword(s):  
Tumor Microenvironment ◽  
Drug Development ◽  
Tumor Model ◽  
Cancer Drug ◽  
Microfluidic Systems ◽  
Anti Cancer

Microfluidic tumor model has the unique advantage of recapitulating tumor microenvironment in a comparatively easier and representative fashion. In this review, we aim to focus more on the possibility of generating clinically actionable information from these microfluidic systems, not just scientific insight.

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