scholarly journals ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas

2020 ◽  
Author(s):  
Lucie Darmusey ◽  
Gaëlle Pérot ◽  
Noémie Thébault ◽  
Sophie Le Guellec ◽  
Nelly Desplat ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Immune Escape ◽  
Adaptive Immune System ◽  
Tumor Growth Rate ◽  
Adaptive Immune ◽  
Expression Of Genes ◽  
Alternative Lengthening ◽  
Poorly Differentiated

AbstractWhole genome and transcriptome sequencing of a cohort of 67 leiomyosarcomas revealed ATRX to be one of the most frequently mutated genes in leiomyosarcomas after TP53 and RB1. While its function is well described in the alternative lengthening of telomeres mechanism, we wondered whether its alteration could have complementary effects on sarcoma oncogenesis. ATRX alteration is associated with the down-expression of genes linked to differentiation in leiomyosarcomas, and to immunity in an additional cohort of 60 poorly differentiated sarcomas. In vitro and in vivo models showed that ATRX loss increases tumor growth rate and immune escape by decreasing the immunity load of active mast cells in sarcoma tumors. These data indicate that an alternative to unsuccessful targeting of the adaptive immune system in sarcoma could be to target the innate system. This might lead to a better outcome for sarcoma patients in terms of ATRX status.

scholarly journals ATRX Alteration Contributes to Tumor Growth and Immune Escape in Pleomorphic Sarcomas

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2151
Author(s):  
Lucie Darmusey ◽  
Gaëlle Pérot ◽  
Noémie Thébault ◽  
Sophie Le Guellec ◽  
Nelly Desplat ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Immune Escape ◽  
Adaptive Immune System ◽  
Tumor Growth Rate ◽  
In Vivo Models ◽  
Expression Of Genes ◽  
Alternative Lengthening ◽  
Poorly Differentiated

Whole genome and transcriptome sequencing of a cohort of 67 leiomyosarcomas has been revealed ATRX to be one of the most frequently mutated genes in leiomyosarcomas after TP53 and RB1. While its function is well described in the alternative lengthening of telomeres mechanism, we wondered whether its alteration could have complementary effects on sarcoma oncogenesis. ATRX alteration is associated with the down-expression of genes linked to differentiation in leiomyosarcomas, and to immunity in an additional cohort of 60 poorly differentiated pleomorphic sarcomas. In vitro and in vivo models showed that ATRX down-expression increases tumor growth rate and immune escape by decreasing the immunity load of active mast cells in sarcoma tumors. These data indicate that an alternative to unsuccessful targeting of the adaptive immune system in sarcoma could target the innate system. This might lead to a better outcome for sarcoma patients in terms of ATRX status.

scholarly journals Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Mauro Di Pilato ◽  
Miguel Palomino-Segura ◽  
Ernesto Mejías-Pérez ◽  
Carmen E. Gómez ◽  
Andrea Rubio-Ponce ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Adaptive Immune System ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Adaptive Immune

AbstractNeutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

Myeloid-derived suppressor cells as a potential treatment target for pancreas adenocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 194-194
Author(s):  
M. R. Porembka ◽  
J. B. Mitchem ◽  
P. S. Goedegebuure ◽  
D. Linehan
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Animal Studies ◽  
Suppressor Cells ◽  
Disease Stage ◽  
Tumor Growth Rate ◽  
Myeloid Derived Suppressor Cells ◽  
Pancreas Adenocarcinoma

194 Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). Here, we quantify MDSC prevalence in patients with PA and assess the efficacy of MDSC depletion in a murine model of PA. Methods: Peripheral blood and tumor samples were collected from patients with PA, analyzed for MDSC (CD15+11b+) by flow cytometry (FC) and compared to cancer-free controls (CFC). The suppressive capacity of MDSC and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid (ZA), a potent aminobisphosphonate previously shown to target MDSC. Endpoints included tumor size, survival, and MDSC prevalence. Tumor cell infiltrate was analyzed by FC for MDSC (Gr1+CD11b+) and effector T cells; tumor cytokine levels were measured by Luminex assay. Results: Patients with PA demonstrated increased circulating MDSC compared to CFC, which correlated with disease stage (metastatic PA: 68%±3.6% of CD45+ cells, resectable PA: 57%±3.5%, CFC: 37%±3.6%; p<0.0001). Normal pancreas tissue showed no MDSC infiltrate while PA avidly recruited CD11b+15+ cells to the primary tumor. Murine tumors similarly recruited MDSC that actively suppressed CD8+ T cells in vitro measured by CFSE dilution and accelerated tumor growth in vivo by adoptive transfer with Pan02 cells (p<0.001). Treatment with ZA impaired MDSC accumulation in the tumor (Placebo: 78%, ZA: 51%, p<0.05) resulting in delayed tumor growth rate (p<0.0001) and prolonged median survival (Placebo: 59 days, ZA: 73 days, p<0.05). MDSC blockade increased recruitment of T cells to the tumor (CD4: 4.4%±1.1% vs 12.2%±2.0%, p<0.05; CD8: 3.9%±1.3% vs 10.6%±2.2%, p<0.05) and a more robust type 1 response with increased levels of IFN-g (p<0.05) and decreased levels of IL-10 (p<0.05). Conclusions: MDSC are an important mediator of tumor-induced immunosuppression in PA. Treatment with ZA effectively blocks MDSC accumulation improving anti-tumor response in animal studies. Efforts to block MDSC may represent a novel treatment strategy for PA. [Table: see text]

scholarly journals RhoGDIα-dependent balance between RhoA and RhoC is a key regulator of cancer cell tumorigenesis

2011 ◽  
Vol 22 (17) ◽  
pp. 3263-3275 ◽  
Author(s):  
T. T. Giang Ho ◽  
Audrey Stultiens ◽  
Johanne Dubail ◽  
Charles M. Lapière ◽  
Betty V. Nusgens ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Progression ◽  
Dynamic Balance ◽  
Cellular Functions ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Interfering Rna

RhoGTPases are key signaling molecules regulating main cellular functions such as migration, proliferation, survival, and gene expression through interactions with various effectors. Within the RhoA-related subclass, RhoA and RhoC contribute to several steps of tumor growth, and the regulation of their expression affects cancer progression. Our aim is to investigate their respective contributions to the acquisition of an invasive phenotype by using models of reduced or forced expression. The silencing of RhoC, but not of RhoA, increased the expression of genes encoding tumor suppressors, such as nonsteroidal anti-inflammatory drug–activated gene 1 (NAG-1), and decreased migration and the anchorage-independent growth in vitro. In vivo, RhoC small interfering RNA (siRhoC) impaired tumor growth. Of interest, the simultaneous knockdown of RhoC and NAG-1 repressed most of the siRhoC-related effects, demonstrating the central role of NAG-1. In addition of being induced by RhoC silencing, NAG-1 was also largely up-regulated in cells overexpressing RhoA. The silencing of RhoGDP dissociation inhibitor α (RhoGDIα) and the overexpression of a RhoA mutant unable to bind RhoGDIα suggested that the effect of RhoC silencing is indirect and results from the up-regulation of the RhoA level through competition for RhoGDIα. This study demonstrates the dynamic balance inside the RhoGTPase network and illustrates its biological relevance in cancer progression.

scholarly journals The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1369
Author(s):  
Mikhail S. Chesnokov ◽  
Imran Khan ◽  
Yeonjung Park ◽  
Jessica Ezell ◽  
Geeta Mehta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Ovarian Carcinoma ◽  
Cell Lines ◽  
Tumor Growth Rate ◽  
High Recurrence Rate ◽  
High Grade ◽  
Serous Ovarian Carcinoma

High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.

Exosome-delivered miR-15a/16 Targets PD-L1 to Inhibit Immune Escape in Gastric Cancer

2021 ◽  
Author(s):  
Changliang Yang ◽  
Qiumo Zhang ◽  
Mengsi Zuo ◽  
Jiayu Yang ◽  
Tao Ning ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Crucial Role ◽  
Immune Escape ◽  
Underlying Mechanism ◽  
Immune Checkpoints

Abstract Recently, immunotherapy targeting immune checkpoints, especially PD-1/PD-L1 blockade, has been demonstrated to play a crucial role in numerous malignancies to rejuvenate disabled T cells to achieve long-term remission. However, the underlying mechanism of PD-L1 expression dysregulation in gastric cancer (GC) has not been revealed. The present study aimed to determine whether artificially modified exosomes transporting miR-15a/16 target PD-L1 and inhibit immune escape in GC. Modified exosomes serve as novel nanoliposomes to suppress tumor growth and inhibit immune escape by targeting PD-L1 in vivo and in vitro. The present study also suggested that the combination of exosomal miR-15a/16 can be used in immunotherapy against tumors, including gastric cancer.

scholarly journals MCM2 and Carbonic Anhydrase 9 Are Novel Potential Targets for Neuroblastoma Pharmacological Treatment

Biomedicines ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 471
Author(s):  
Patrizia Garbati ◽  
Raffaella Barbieri ◽  
Davide Cangelosi ◽  
Carlo Zanon ◽  
Delfina Costa ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Carbonic Anhydrase ◽  
Tumor Growth ◽  
Cell Model ◽  
Tumor Growth Rate ◽  
In Vivo Models ◽  
Gene Sets ◽  
Carbonic Anhydrase 9

To overcome the lack of effective pharmacological treatments for high-risk neuroblastoma (HR-NB), the development of novel in vitro and in vivo models that better recapitulate the disease is required. Here, we used an in vitro multiclonal cell model encompassing NB cell differentiation stages, to identify potential novel pharmacological targets. This model allowed us to identify, by low-density RT-PCR arrays, two gene sets, one over-expressed during NB cell differentiation, and the other up-regulated in more malignant cells. Challenging two HR-NB gene expression datasets, we found that these two gene sets are related to high and low survival, respectively. Using mouse NB cisplatin-treated xenografts, we identified two genes within the list associated to the malignant stage (MCM2 and carbonic anhydrase 9), whose expression is positively correlated with tumor growth. Thus, we tested their pharmacological targeting as potential therapeutic strategy. We measured mice survival and tumor growth rate after xenografts of human NB treated with cisplatin in the presence of MCM2/carbonic anhydrase 9 inhibitors (ciprofloxacin and acetazolamide). MCM2 or carbonic anhydrase 9 inhibition significantly increased cisplatin activity, supporting their possible testing for NB therapy.

scholarly journals Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy

2020 ◽  
Vol 117 (12) ◽  
pp. 6640-6650 ◽  
Author(s):  
Xiaodong Wang ◽  
Xiaohui Yang ◽  
Chang Zhang ◽  
Yang Wang ◽  
Tianyou Cheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Colony Formation ◽  
Immune Escape ◽  
Potential Biomarker

The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

Chemokines in tumor-associated angiogenesis

2009 ◽  
Vol 390 (12) ◽  
Author(s):  
Peter Arne Gerber ◽  
Andreas Hippe ◽  
Bettina Alexandra Buhren ◽  
Anja Müller ◽  
Bernhard Homey
Keyword(s):  
Tumor Growth ◽  
Immune Escape ◽  
De Novo ◽  
Vascular Endothelial ◽  
Key Factors ◽  
Endothelial Growth Factor ◽  
Bidirectional Interactions ◽  
G Protein Coupled

AbstractTumor growth is dependent on several key factors. Apart from immune escape and an efficient blockade of apoptotic signals, tumors require oxygen and nutrients to grow past a diameter of 2 μm. Therefore, it is of vital importance for the tumor to facilitate tumor-associated angiogenesis, e.g., thede novoformation of new blood vessels. In addition to established and key angiogenic factors, such as vascular endothelial growth factor, chemokines, a superfamily of cytokine-like proteins that bind to seven transmembrane-spanning G-protein-coupled receptors, have been associated with angiogenesis under homeostatic conditions. Chemokines were initially identified as key factors that control the directional migration of leukocytes, stem cells and cancer cellsin vitroand which critically regulate their traffickingin vivo. Recently their role in establishing a favorable microenvironment for tumor-associated angiogenesis, a process that requires complex bidirectional interactions of the tumor and associated vessels, has been the focus of research. Chemokine-promoted angiogenesis not only facilitates tumor growth by supplying nutrients and oxygen but it is also a prerequisite to tumor metastasis. Hence, the pharmacologic control of tumor angiogenesis presents a promising strategy for novel anticancer therapeutics. Here, we discuss the current pathogenetic concepts of tumor-associated angiogenesis in the context of chemokines and their receptors and highlight promising therapeutic strategies.

scholarly journals Adaptive Immune Response to Model Antigens Is Impaired in Murine Leukocyte-Adhesion Deficiency-1 Revealing Elevated Activation ThresholdsIn Vivo

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Thorsten Peters ◽  
Wilhelm Bloch ◽  
Oliver Pabst ◽  
Claudia Wickenhauser ◽  
Claudia Uthoff-Hachenberg ◽  
...  
Keyword(s):  
Immune Responses ◽  
Leukocyte Adhesion ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Leukocyte Adhesion Deficiency ◽  
Protein Ratio ◽  
Adaptive Immune ◽  
Immunodeficiency Syndrome

Absence ofβ2integrins (CD11/CD18) leads to leukocyte-adhesion deficiency-1 (LAD1), a rare primary immunodeficiency syndrome. Although extensivein vitrowork has established an essential function ofβ2integrins in adhesive and signaling properties for cells of the innate and adaptive immune system, their respective participation in an altered adaptive immunity in LAD1 patients are complex and only partly understoodin vivo. Therefore, we investigated adaptive immune responses towards different T-dependent antigens in a murine LAD1 model ofβ2integrin-deficiency (CD18−/−). CD18−/−mice generated only weak IgG responses after immunization with tetanus toxoid (TT). In contrast, robust hapten- and protein-specific immune responses were observed after immunization with highly haptenated antigens such as (4-hydroxy-3-nitrophenyl)21acetyl chickenγglobulin (NP21-CG), even though regularly structured germinal centers with specificity for the defined antigens/haptens in CD18−/−mice remained absent. However, a decrease in the hapten/protein ratio lowered the efficacy of immune responses in CD18−/−mice, whereas a mere reduction of the antigen dose was less crucial. Importantly, haptenation of TT with NP (NP-TT) efficiently restored a robust IgG response also to TT. Our findings may stimulate further studies on a modification of vaccination strategies using highly haptenated antigens in individuals suffering from LAD1.

Sign in / Sign up

Export Citation Format

Share Document