scholarly journals Targeting TIGIT Inhibits Bladder Cancer Metastasis Through Suppressing IL-32

2022 ◽  
Vol 12 ◽  
Author(s):  
Kang Wu ◽  
Jun Zeng ◽  
Xulian Shi ◽  
Jiajia Xie ◽  
Yuqing Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
Cancer Metastasis ◽  
Cytotoxic T Lymphocyte ◽  
Metastatic Tumor ◽  
Treg Cells ◽  
Antitumor Immune Response ◽  
Immune Checkpoints ◽  
Promoting Effect ◽  
Novel Target

Bladder cancer is a highly metastatic tumor and one of the most common malignancies originating in the urinary tract. Despite the efficacy of immune checkpoints, including programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), the effect of immunotherapy for bladder cancer remains unsatisfactory. Therefore, it is urgent to develop new targets to expand immunotherapeutic options. In this study, we utilized single-cell sequencing to explore the cell composition of tumors and detected a subset of Treg cells with high expression of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and interleukin (IL)-32. The antitumor immune response was suppressed by this subset of Treg cells, while IL-32 promoted bladder cancer metastasis. Nevertheless, targeting TIGIT not only reversed immunosuppression by restoring the antitumor immune response mediated by T cells but also suppressed the secretion of IL-32 and inhibited the metastasis of bladder cancer cells. Thus, our study provided novel insights into immunosuppression in bladder cancer and highlighted TIGIT as a novel target for immunotherapy of bladder cancer. We also illustrated the mechanism of the dual effect of targeting TIGIT and revealed the metastasis-promoting effect of IL-32 in bladder cancer. Collectively, these findings raise the possibility of utilizing TIGIT as a target against bladder cancer from the bench to the bedside.

Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors

2006 ◽  
Vol 105 (3) ◽  
pp. 430-437 ◽  
Author(s):  
Abdeljabar El Andaloussi ◽  
Yu Han ◽  
Maciej S. Lesniak
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Brain Tumors ◽  
Malignant Gliomas ◽  
Tumor Infiltrating Lymphocytes ◽  
Treg Cells ◽  
Separate Experiment ◽  
The Central Nervous System ◽  
Novel Target ◽  
Infiltrating Lymphocytes

Object Regulatory CD4+CD25+ T cells have been shown to play an important role in the regulation of the immune response. Whereas the presence of these cells has been associated with immune suppression, the lack of regulatory T (Treg) cells has been shown to induce autoimmunity. The purpose of this study was to define the role of Treg cells in tumors of the central nervous system (CNS). Methods The authors implanted syngeneic GL261 tumor cells in the brains or flanks of C57BL/6 mice. The resulting tumors were later removed at specific time points, and the presence of tumor-infiltrating lymphocytes was analyzed by performing flow cytometry for the presence of Treg cells. In a separate experiment, mice with GL261 tumors were treated with injections of anti-CD25 monoclonal antibody (mAb) to determine whether depletion of Treg cells may have an impact on the length of survival in mice with brain tumors. Tumor-infiltrating lymphocytes isolated from mice with GL261 tumors were found to have a significant increase in the presence of Treg cells compared with control lymphocytes (p < 0.05). Moreover, Treg cells isolated in murine brain tumors expressed FoxP3, CTLA-4, and CD62L. Mice treated with anti-CD25 mAb lived significantly longer than tumor-bearing control animals (p < 0.05). An analysis of brains in surviving animals showed a depletion of CD4+CD25+ T cells. Conclusions The results of this study indicate that CD4+CD25+ Treg cells play an important role in suppressing the immune response to CNS tumors. These Treg cells may therefore represent a potentially novel target for immunotherapy of malignant gliomas.

scholarly journals Targeting Immune Signaling Checkpoints in Acute Myeloid Leukemia

2019 ◽  
Vol 8 (2) ◽  
pp. 236 ◽  
Author(s):  
Krzysztof Giannopoulos
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Negative Control ◽  
Immune Checkpoints ◽  
Hematopoietic Stem ◽  
Acute Myeloid

The modest successes of targeted therapies along with the curative effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) in acute myeloid leukemia (AML) stimulate the development of new immunotherapies. One of the promising methods of immunotherapy is the activation of immune response by the targeting of negative control checkpoints. The two best-known inhibitory immune checkpoints are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 receptor (PD-1). In AML, PD-1 expression is observed in T-cell subpopulations, including T regulatory lymphocytes. Increased PD-1 expression on CD8+ T lymphocytes may be one of the factors leading to dysfunction of cytotoxic T cells and inhibition of the immune response during the progressive course of AML. Upregulation of checkpoint molecules was observed after alloHSCT and therapy with hypomethylating agents, pointing to a potential clinical application in these settings. Encouraging results from recent clinical trials (a response rate above 50% in a relapsed setting) justify further clinical use. The most common clinical trials employ two PD-1 inhibitors (nivolumab and pembrolizumab) and two anti-PD-L1 (programmed death-ligand 1) monoclonal antibodies (atezolizumab and durvalumab). Several other inhibitors are under development or in early phases of clinical trials. The results of these clinical trials are awaited with great interest in, as they may allow for the established use of checkpoint inhibitors in the treatment of AML.

scholarly journals Stability Analysis of Delayed Immune Response BCG Infection in Bladder Cancer Treatment Model by Stochastic Perturbations

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Leonid Shaikhet ◽  
Svetlana Bunimovich-Mendrazitsky
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
Cytotoxic T Lymphocyte ◽  
Logistic Growth ◽  
Cancer Cell Proliferation ◽  
Stochastic Perturbations ◽  
Proposed Model ◽  
Integral Element ◽  
Improved Model ◽  
General Method

We present a revised mathematical model of the immune response to Bacillus Calmette-Guérin (BCG) treatment of bladder cancer, optimized according to biological and clinical data accumulated during the last decade. The improved model accounts for cytotoxic T lymphocyte differentiation as an integral element of the delayed immune response, as well as the logistic growth terms for cancer cell proliferation. Three equilibria are demonstrated for the proposed model, which is assumed to be influenced by white noise stochastic perturbations that are directly proportional to the system state deviation from an equilibrium. Stability conditions for all equilibria are analyzed using the Kolmanovskii-Shaikhet general method of Lyapunov functionals construction.

scholarly journals Dynamics of Immune Checkpoints, Immune System, and BCG in the Treatment of Superficial Bladder Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Farouk Tijjani Saad ◽  
Evren Hincal ◽  
Bilgen Kaymakamzade
Keyword(s):  
Bladder Cancer ◽  
Immune System ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Superficial Bladder Cancer ◽  
Cytotoxic T Lymphocyte ◽  
Immunological Tolerance ◽  
Immune Checkpoints ◽  
Self Tolerance ◽  
Cell Death Protein

This paper aims to study the dynamics of immune suppressors/checkpoints, immune system, and BCG in the treatment of superficial bladder cancer. Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and transforming growth factor-beta (TGF-β) are some of the examples of immune suppressors/checkpoints. They are responsible for deactivating the immune system and enhancing immunological tolerance. Moreover, they categorically downregulate and suppress the immune system by preventing and blocking the activation of T-cells, which in turn decreases autoimmunity and enhances self-tolerance. In cancer immunotherapy, the immune checkpoints/suppressors prevent and block the immune cells from attacking, spreading, and killing the cancer cells, which leads to cancer growth and development. We formulate a mathematical model that studies three possible dynamics of the treatment and establish the effects of the immune checkpoints on the immune system and the treatment at large. Although the effect cannot be seen explicitly in the analysis of the model, we show it by numerical simulations.

scholarly journals Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Marina Gazdic ◽  
Bojana Simovic Markovic ◽  
Nemanja Jovicic ◽  
Maja Misirkic-Marjanovic ◽  
Valentin Djonov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lung Cancer ◽  
Stem Cells ◽  
Immune Response ◽  
Mesenchymal Stem Cells ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Cancer Metastasis ◽  
Antitumor Immune Response ◽  
Lung Cancer Metastasis

Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases.

scholarly journals Galectin-9/TIM-3 as a Key Regulator of Immune Response in Gliomas With Chromosome 1p/19q Codeletion

2021 ◽  
Vol 12 ◽  
Author(s):  
Guanzhang Li ◽  
Ruoyu Huang ◽  
Wenhua Fan ◽  
Di Wang ◽  
Fan Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Responses ◽  
The Cancer Genome Atlas ◽  
Antitumor Immune Response ◽  
Immune Checkpoints ◽  
Sequencing Data ◽  
Chromosome 1P ◽  
Genome Atlas

Gliomas with chromosome 1p/19q codeletion were considered a specific tumor entity. This study was designed to reveal the biological function alterations tightly associated with 1p/19q codeletion in gliomas. Clinicopathological and RNA sequencing data from glioma patients were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Gene set variation analysis was performed to explore the differences in biological functions between glioma subgroups stratified by 1p/19q codeletion status. The abundance of immune cells in each sample was detected using the CIBERSORT analytical tool. Single-cell sequencing data from public databases were analyzed using the t-distributed stochastic neighbor embedding (t-SNE) algorithm, and the findings were verified by in vitro and in vivo experiments and patient samples.We found that the activation of immune and inflammatory responses was tightly associated with 1p/19q codeletion in gliomas. As the most important transcriptional regulator of Galectin-9 in gliomas, the expression level of CCAAT enhancer-binding protein alpha in samples with 1p/19q codeletion was significantly decreased, which led to the downregulation of the immune checkpoints Galectin-9 and TIM-3. These results were validated in three independent datasets. The t-SNE analysis showed that the loss of chromosome 19q was the main reason for the promotion of the antitumor immune response. IHC protein staining, in vitro and in vivo experiments verified the results of bioinformatics analysis. In gliomas, 1p/19q codeletion can promote the antitumor immune response by downregulating the expression levels of the immune checkpoint TIM-3 and its ligand Galectin-9.

scholarly journals Tasquinimod modulates tumor-infiltrating myeloid cells and improves the antitumor immune response to PD-L1 blockade in bladder cancer

2016 ◽  
Vol 5 (6) ◽  
pp. e1145333 ◽  
Author(s):  
Jessica Nakhlé ◽  
Valérie Pierron ◽  
Anne-Laure Bauchet ◽  
Pascale Plas ◽  
Amath Thiongane ◽  
...  
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
Myeloid Cells ◽  
Antitumor Immune Response

scholarly journals Inflammatory Markers in Cancer Immunotherapy

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 325
Author(s):  
Deepak Ravindranathan ◽  
Viraj A. Master ◽  
Mehmet Asim Bilen
Keyword(s):  
Immune Response ◽  
Inflammatory Markers ◽  
Inflammatory Responses ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Systemic Circulation ◽  
Response To Therapy ◽  
Immune Checkpoints ◽  
Reactive Protein ◽  
Tumor Environment

Chronic inflammation is considered a major risk factor for cancer formation. Inflammation within the tumor environment plays a role in its response to therapy, growth, and prognosis. Cancer associated inflammation is known to occur in the tumor microenvironment and in the systemic circulation, and is correlated with disease progression and prognosis in many cancers. Blood cells such as neutrophils, lymphocytes, platelets, and circulating proteins such as C-reactive protein, and interleukins, such as IL-6, have been associated with inflammatory responses, which contribute to tumorigenesis. Cancer has found ways to evade the immune response; a pathway that can attenuate the innate immune response is via blocking immune checkpoints. Development of monoclonal antibodies against inhibitory immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have given rise to immunotherapy, which has shown remarkable responses in anti-tumor activity resulting in several U.S. Federal and Drug Administration (FDA)-approved checkpoint inhibitors. Various inflammatory markers and their prognostic and predictive implications in malignancies treated with immunotherapy will be discussed in this review.

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