scholarly journals The Role of Dectin-1 Signaling in Altering Tumor Immune Microenvironment in the Context of Aging

2021 ◽  
Vol 11 ◽  
Author(s):  
Natarajan Bhaskaran ◽  
Sangeetha Jayaraman ◽  
Cheriese Quigley ◽  
Prerna Mamileti ◽  
Mahmoud Ghannoum ◽  
...  
Keyword(s):  
Potential Role ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Tumor Burden ◽  
Aged Mice ◽  
Fungal Abundance ◽  
Tumor Immune Microenvironment ◽  
Deficient Mice ◽  
Partial Depletion

An increased accumulation of immune-dysfunction-associated CD4+Foxp3+ regulatory T cells (Tregs) is observed in aging oral mucosa during infection. Here we studied the function of Tregs during oral cancer development in aging mucosa. First, we found heightened proportions of Tregs and myeloid-derived suppressor cells (MDSC) accumulating in mouse and human oral squamous cell carcinoma (OSCC) tissues. Using the mouse 4-Nitroquinoline 1-oxide(4-NQO) oral carcinogenesis model, we found that tongues of aged mice displayed increased propensity for epithelial cell dysplasia, hyperplasia, and accelerated OSCC development, which coincided with significantly increased abundance of IL-1β, Tregs, and MDSC in tongues. Partial depletion of Tregs reduced tumor burden. Moreover, fungal abundance and dectin-1 signaling were elevated in aged mice suggesting a potential role for dectin-1 in modulating immune environment and tumor development. Confirming this tenet, dectin-1 deficient mice showed diminished IL-1β, reduced infiltration of Tregs and MDSC in the tongues, as well as slower progression and reduced severity of tumor burden. Taken together, these data identify an important role of dectin-1 signaling in establishing the intra-tumoral immunosuppressive milieu and promoting OSCC tumorigenesis in the context of aging.

scholarly journals The role of dectin-1 signaling in altering tumor immune microenvironment in the context of aging

2021 ◽  
Author(s):  
Natarajan Bhaskaran ◽  
Sangeetha Jayaraman ◽  
Cheriese Quigley ◽  
Prerna Mamileti ◽  
Mahmoud Ghannoum ◽  
...  
Keyword(s):  
Potential Role ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Tumor Burden ◽  
Aged Mice ◽  
Fungal Abundance ◽  
Tumor Immune Microenvironment ◽  
Deficient Mice ◽  
Partial Depletion

AbstractAn increased accumulation of immune-dysfunction-associated CD4+Foxp3+ regulatory T cells (Tregs) is observed in aging oral mucosa during infection. Here we studied the function of Tregs during oral cancer development in aging mucosa. First, we found heightened proportions of Tregs and myeloid-derived suppressor cells (MDSC) accumulating in mouse and human oral squamous cell carcinoma (OSCC) tissues. Using the mouse 4-Nitroquinoline 1-oxide(4-NQO) oral carcinogenesis model, we found that tongues of aged mice displayed increased propensity for epithelial cell dysplasia, hyperplasia, and accelerated OSCC development, which coincided with significantly increased abundance of IL-1β, Tregs, and MDSC in tongues. Partial depletion of Tregs reduced tumor burden. Moreover, fungal abundance and dectin-1 signaling were elevated in aged mice suggesting a potential role for dectin-1 in modulating immune environment and tumor development. Confirming this tenet, dectin-1 deficient mice showed diminished IL-1β, reduced infiltration of Tregs and MDSC in the tongues, as well as slower progression and reduced severity of tumor burden. Taken together, these data identify an important role of dectin-1 signaling in establishing the intra-tumoral immunosuppressive milieu and promoting OSCC tumorigenesis in the context of aging.

IMMU-22. THE IMPACT OF MICROGLIA MODULATION ON GBM PROGRESSION IN SYNGENEIC MOUSE MODELS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi96-vi96
Author(s):  
Marie-Françoise Ritz ◽  
Tala Shekarian ◽  
Tomás A Martins ◽  
Philip Schmassmann ◽  
Gregor Hutter
Keyword(s):  
Mouse Models ◽  
Tumor Development ◽  
Adaptive Immune Response ◽  
Tamoxifen Treatment ◽  
Mouse Strains ◽  
Intracerebral Injection ◽  
Adaptive Immune ◽  
Tumor Immune Microenvironment ◽  
The Impact

Abstract BACKGROUND The tumor immune microenvironment (TME) of Glioblastoma consists of almost myeloid-derived macrophages and microglia called TAMs. We have shown that the disruption of CD47-Sirpα-axis induces an antitumor activity of TAMs against GBM in immune-deficient mice, through increases of phagocytosis of tumor cells by TAMs. We have aimed to study the role of microglia and its activation/depletion on GBM progression, in the syngeneic GBM model in immune-competent mice. We have studied the interplay of innate and adaptive immune response after activation and depletion of microglia and the effect on tumor progression and outcome of the mice. MATERIAL AND METHODS We used different colonies of genetically modified immunocompetent mouse strains to genetically activate/deplete microglia in the tumor context. We generated Sall1 CreERT2/fl mice and Cre-negative littermates. The application of Tamoxifen in this constellation leads to the excision of the transcription factor Sall1 and subsequent enhanced microglia activity. Conversely, we generated Sall1 CreERT2 x Csf1r fl/fl animals and the respective heterozygous and Cre-negative littermates in which Tamoxifen treatment leads to inactivation of microglia through the deletion of Csf1r. Glioblastoma tumors were induced by intracerebral injection of GL261, CT2A, or retrovirus-induced PDGF-Akt in pups and Tamoxifen treatment was started once the tumors were detected. RESULTS We observed a survival advantage in tumor-bearing mice after activation of microglia in Sall1 CreERT/fl animals compared to Cre-negative littermates. Genetic depletion of microglia in this model resulted in a shorter lifespan in microglia-depleted animals compared to Cre-negative littermates. Furthermore, the iTME in these tumors is subjected to scRNAseq analysis to identify mechanistic insights. CONCLUSION Microglia are important players in tumor development and progression of glioblastoma in mouse models. These cells may be targeted in future immunotherapeutic approaches for patients.

scholarly journals Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3631
Author(s):  
Krystal Villalobos-Ayala ◽  
Ivannie Ortiz Rivera ◽  
Ciara Alvarez ◽  
Kazim Husain ◽  
DeVon DeLoach ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Responses ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Tumor Burden ◽  
Sh2 Domain ◽  
Src Homology 2 ◽  
Src Homology ◽  
And Function ◽  
Deficient Mice

Pancreatic cancer (PC) has an extremely poor prognosis due to the expansion of immunosuppressive myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the inflammatory tumor microenvironment (TME), which halts the recruitment of effector immune cells and renders immunotherapy ineffective. Thus, the identification of new molecular targets that can modulate the immunosuppressive TME is warranted for PC intervention. Src Homology-2 (SH2) domain-containing Inositol 5′-Phosphatase-1 (SHIP-1) is a lipid signaling protein and a regulator of myeloid cell development and function. Herein, we used the bioflavonoid apigenin (API) to reduce inflammation in different PC models. Wild type mice harboring heterotopic or orthotopic PC were treated with API, which induced SHIP-1 expression, reduced inflammatory tumor-derived factors (TDF), increased the proportion of tumoricidal macrophages and enhanced anti-tumor immune responses, resulting in a reduction in tumor burden compared to vehicle-treated PC mice. In contrast, SHIP-1-deficient mice exhibited an increased tumor burden and displayed augmented proportions of pro-tumor macrophages. These results provide further support for the importance of SHIP-1 expression in promoting pro-tumor macrophage development in the pancreatic TME. Our findings suggest that agents augmenting SHIP-1 expression may provide novel therapeutic options for the treatment of PC.

scholarly journals Impaired thrombin generation in Reelin-deficient mice: a potential role of plasma Reelin in hemostasis

2014 ◽  
Vol 12 (12) ◽  
pp. 2054-2064 ◽  
Author(s):  
W.-L. Tseng ◽  
T.-H. Chen ◽  
C.-C. Huang ◽  
Y.-H. Huang ◽  
C.-F. Yeh ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Potential Role ◽  
Deficient Mice

scholarly journals Potential Role of the Chemokine Macrophage Inflammatory Protein 1α in Human and Experimental Schistosomiasis

2005 ◽  
Vol 73 (4) ◽  
pp. 2515-2523 ◽  
Author(s):  
Adriano L. S. Souza ◽  
Ester Roffê ◽  
Vanessa Pinho ◽  
Danielle G. Souza ◽  
Adriana F. Silva ◽  
...  
Keyword(s):  
Potential Role ◽  
Severe Disease ◽  
Experimental Studies ◽  
Interleukin 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Deficient Mice

ABSTRACT In human schistosomiasis, the concentrations of the chemokine macrophage inflammatory protein 1α (MIP-1α/CCL3) is greater in the plasma of patients with clinical hepatosplenic disease. The objective of the present study was to confirm the ability of CCL3 to detect severe disease in patients classified by ultrasonography (US) and to evaluate the potential role of CCL3 in Schistosoma mansoni-infected mice. CCL3 was measured by enzyme-linked immunosorbent assay in the plasma of S. mansoni-infected patients. CCL3-deficient mice were infected with 25 cercariae, and various inflammatory and infectious indices were evaluated. The concentration of CCL3 was higher in the plasma of S. mansoni-infected than noninfected patients. Moreover, CCL3 was greater in those with US-defined hepatosplenic than with the intestinal form of the disease. In CCL3-deficient mice, the size of the granuloma and the liver eosinophil peroxidase activity and collagen content were diminished compared to wild-type mice. In CCL3-deficient mice, the worm burden after 14 weeks of infection, but not after 9 weeks, was consistently smaller. The in vitro response of mesenteric lymph node cells to antigen stimulation was characterized by lower levels of interleukin-4 (IL-4) and IL-10. CCL3 is a marker of disease severity in infected humans, and experimental studies in mice suggest that CCL3 may be a causative factor in the development of severe schistosomiasis.

scholarly journals BACE1 partial deletion induces synaptic plasticity deficit in adult mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sylvia Lombardo ◽  
Martina Chiacchiaretta ◽  
Andrew Tarr ◽  
WonHee Kim ◽  
Tingyi Cao ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Axonal Guidance ◽  
Knock Out ◽  
App Processing ◽  
Aged Mice ◽  
Adult Mice ◽  
Term Potentiation ◽  
Partial Depletion

AbstractBACE1 is the first enzyme involved in APP processing, thus it is a strong therapeutic target candidate for Alzheimer’s disease. The observation of deleterious phenotypes in BACE1 Knock-out (KO) mouse models (germline and conditional) raised some concerns on the safety and tolerability of BACE1 inhibition. Here, we have employed a tamoxifen inducible BACE1 conditional Knock-out (cKO) mouse model to achieve a controlled partial depletion of BACE1 in adult mice. Biochemical and behavioural characterization was performed at two time points: 4–5 months (young mice) and 12–13 months (aged mice). A ~50% to ~70% BACE1 protein reduction in hippocampus and cortex, respectively, induced a significant reduction of BACE1 substrates processing and decrease of Aβx-40 levels at both ages. Hippocampal axonal guidance and peripheral nerve myelination were not affected. Aged mice displayed a CA1 long-term potentiation (LTP) deficit that was not associated with memory impairment. Our findings indicate that numerous phenotypes observed in germline BACE1 KO reflect a fundamental role of BACE1 during development while other phenotypes, observed in adult cKO, may be absent when partially rather than completely deleting BACE1. However, we demonstrated that partial depletion of BACE1 still induces CA1 LTP impairment, supporting a role of BACE1 in synaptic plasticity in adulthood.

scholarly journals Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 780
Author(s):  
Kishor Pant ◽  
Estanislao Peixoto ◽  
Seth Richard ◽  
Sergio A. Gradilone
Keyword(s):  
Histone Deacetylases ◽  
Potential Role ◽  
Chemotherapy Resistance ◽  
Tumor Development ◽  
Therapeutic Targets ◽  
Cellular Proteins ◽  
Epigenetic Changes ◽  
Post Translational Modifications ◽  
Frequent Relapse

Cholangiocarcinoma (CCA) is a highly invasive and metastatic form of carcinoma with bleak prognosis due to limited therapies, frequent relapse, and chemotherapy resistance. There is an urgent need to identify the molecular regulators of CCA in order to develop novel therapeutics and advance diseases diagnosis. Many cellular proteins including histones may undergo a series of enzyme-mediated post-translational modifications including acetylation, methylation, phosphorylation, sumoylation, and crotonylation. Histone deacetylases (HDACs) play an important role in regulating epigenetic maintenance and modifications of their targets, which in turn exert critical impacts on chromatin structure, gene expression, and stability of proteins. As such, HDACs constitute a group of potential therapeutic targets for CCA. The aim of this review was to summarize the role that HDACs perform in regulating epigenetic changes, tumor development, and their potential as therapeutic targets for CCA.

scholarly journals Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Simon Milette ◽  
Masakazu Hashimoto ◽  
Stephanie Perrino ◽  
Shu Qi ◽  
Michely Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Sexual Dimorphism ◽  
Liver Metastases ◽  
Suppressor Cells ◽  
Cytotoxic T Cell ◽  
Immune Microenvironment ◽  
Ovariectomized Mice ◽  
Cell Accumulation ◽  
Tumor Immune Microenvironment

AbstractLiver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8+ T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.

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