scholarly journals The Potential of Combining Tubulin-Targeting Anticancer Therapeutics and Immune Therapy

2019 ◽  
Vol 20 (3) ◽  
pp. 586 ◽  
Author(s):  
Alexis Fong ◽  
Amanda Durkin ◽  
Hoyun Lee
Keyword(s):  
Anticancer Agents ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Immune Therapy ◽  
Cell Types ◽  
Treg Cells ◽  
Dendritic Cell Maturation ◽  
Microtubule Inhibitors ◽  
M1 Macrophage ◽  
Effective Option

Cancer immune therapy has recently shown tremendous promise to combat many different cancers. The microtubule is a well-defined and very effective cancer therapeutic target. Interestingly, several lines of evidence now suggest that microtubules are intimately connected to the body’s immune responses. This raises the possibility that the combination of microtubule inhibitors and immune therapy can be a highly effective option for cancer treatments. However, our understanding on this potentially important aspect is still very limited, due in part to the multifaceted nature of microtubule functions. Microtubules are not only involved in maintaining cell morphology, but also a variety of cellular processes, including the movement of secretory vesicles and organelles, intracellular macromolecular assembly, signaling pathways, and cell division. Microtubule inhibitors may be subdivided into two classes: Anti-depolymerization agents such as the taxane family, and anti-polymerization agents such as colchicine and vinka alkaloids. These two different classes may have different effects on immune cell subtypes. Anti-depolymerization agents can not only induce NK cells, but also appear to inhibit T regulatory (Treg) cells. However, different inhibitors may have different functions even among the same class. For example, the doxetaxel anti-depolymerization agent up-regulates cytotoxic T cells, while paclitaxel down-regulates them. Certain anti-polymerization agents such as colchicine appear to down-regulate most immune cell types, while inducing dendritic cell maturation and increasing M1 macrophage population. In contrast, the vinblastine anti-polymerization agent activates many of these cell types, albeit down-regulating Treg cells. In this review, we focus on the various effects of tubulin inhibitors on the activities of the body’s immune system, in the hope of paving the way to develop an effective cancer therapy by combining tubulin-targeting anticancer agents and immune therapy.

scholarly journals Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 450 ◽  
Author(s):  
Saeed Daneshmandi ◽  
Barbara Wegiel ◽  
Pankaj Seth
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Lactate Dehydrogenase ◽  
Programmed Cell Death ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Treg Cells ◽  
Interferon Γ ◽  
Mitochondrial Activity ◽  
Small Subset

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients. We have recently reported that programmed cell death protein-1 (PD-1) ligand (PD-L1) expression is regulated by lactate present at high levels in the tumor microenvironment (TME). We hypothesized that the efficacy of anti-PD-1 treatment can be improved by blocking the lactate-generating enzyme, lactate dehydrogenase-A (LDH-A). Anti-PD-1 treatment of mice harboring LDH-A deficient B16-F10 melanoma tumors led to an increase in anti-tumor immune responses compared to mice implanted with tumors expressing LDH-A. Specifically, we observed heightened infiltration of natural killer (NK) cells and CD8+ cytotoxic T cells in the LDH-A deficient tumors. These infiltrated cytotoxic cells had an elevated production of interferon-γ (IFN-γ) and granzyme B. Mechanistically, CD8+ T cells isolated from the TME of LDH-A deficient B16-F10 melanoma tumors and treated with anti-PD-1 showed enhanced mitochondrial activity and increased reactive oxygen species (ROS) levels. Moreover, infiltration of T regulatory (Treg) cells was diminished in LDH-A deficient tumors treated with anti-PD-1. These altered immune cell profiles were clinically relevant as they were accompanied by significantly reduced tumor growth. Our study suggests that blocking LDH-A in the tumor might improve the efficacy of anti-PD-1 therapy.

Cefdinir Microsphere Modulated Microflora and Liver Immunological Response to Diet Induced Diabetes in Mice

2019 ◽  
Vol 19 (3) ◽  
pp. 349-357 ◽  
Author(s):  
Sweta Patel ◽  
Dipeeka Mandaliya ◽  
Bhumika Prajapati ◽  
Sunny Kumar ◽  
Sriram Seshadri
Keyword(s):  
Insulin Sensitivity ◽  
Metabolic Disorders ◽  
Immune Cell ◽  
Immunological Response ◽  
Cell Types ◽  
Treg Cells ◽  
Liver Trauma ◽  
Mice Model ◽  
Gut Flora ◽  
Diabetes In Mice

Objective: Gut microbiota is currently targeted for various diseases especially metabolic disorders such as diabetes. Our strategy is to alter gut microflora via specific antibiotic to reduce load of inflammation in the liver that increases as a result of high carbohydrate diet. Th1, Th17 and Treg are important immune cell types which decide the type of inflammatory response. Liver is tolerogenic in nature with low Th17/Treg ratio. In diabetics, this ratio decreases even more, and can cause liver trauma. Method: The present study tries to find relationship between gut flora and immune cells such as Th1/Th17/Treg and their role in liver metabolism using diet induced diabetic mice model. Result: Upon alteration of flora using Cefdinir in different forms, one could help lower the level of Treg cells thus increasing the ratio. Gut flora is strongly associated with the immunity in the liver. Targeted alteration of gut flora helps us to restore insulin sensitivity. Conclusion: Colon targeted Cefdinir gives more promising results, opens colonic bacteria as target for improving gut, liver inflammation and insulin sensitivity.

scholarly journals Immunostimulatory Properties of Chemotherapy in Breast Cancer: From Immunogenic Modulation Mechanisms to Clinical Practice

2022 ◽  
Vol 12 ◽  
Author(s):  
Jinguo Zhang ◽  
Shuaikang Pan ◽  
Chen Jian ◽  
Li Hao ◽  
Jie Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Suppressor Cells ◽  
Treg Cells ◽  
Immune Effector ◽  
Chemotherapy Drugs ◽  
Cytotoxic Treatment

Breast cancer (BC) is the most common malignancy among females. Chemotherapy drugs remain the cornerstone of treatment of BC and undergo significant shifts over the past 100 years. The advent of immunotherapy presents promising opportunities and constitutes a significant complementary to existing therapeutic strategies for BC. Chemotherapy as a cytotoxic treatment that targets proliferation malignant cells has recently been shown as an effective immune-stimulus in multiple ways. Chemotherapeutic drugs can cause the release of damage-associated molecular patterns (DAMPs) from dying tumor cells, which result in long-lasting antitumor immunity by the key process of immunogenic cell death (ICD). Furthermore, Off-target effects of chemotherapy on immune cell subsets mainly involve activation of immune effector cells including natural killer (NK) cells, dendritic cells (DCs), and cytotoxic T cells, and depletion of immunosuppressive cells including Treg cells, M2 macrophages and myeloid-derived suppressor cells (MDSCs). Current mini-review summarized recent large clinical trials regarding the combination of chemotherapy and immunotherapy in BC and addressed the molecular mechanisms of immunostimulatory properties of chemotherapy in BC. The purpose of our work was to explore the immune-stimulating effects of chemotherapy at the molecular level based on the evidence from clinical trials, which might be a rationale for combinations of chemotherapy and immunotherapy in BC.

scholarly journals Immune Cell Types and Secreted Factors Contributing to Inflammation-to-Cancer Transition and Immune Therapy Response

Cell Reports ◽  
2019 ◽  
Vol 26 (7) ◽  
pp. 1965-1977.e4 ◽  
Author(s):  
Xingwei Chen ◽  
Chi Xu ◽  
Shengjun Hong ◽  
Xian Xia ◽  
Yaqiang Cao ◽  
...  
Keyword(s):  
Immune Cell ◽  
Immune Therapy ◽  
Therapy Response ◽  
Cell Types ◽  
Secreted Factors

scholarly journals Identification of Immune-Related Key Genes in Ovarian Cancer Based on WGCNA

2021 ◽  
Vol 12 ◽  
Author(s):  
Qingli Quan ◽  
Xinxin Xiong ◽  
Shanyun Wu ◽  
Meixing Yu
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Treg Cells ◽  
M1 Macrophages ◽  
Γδt Cells ◽  
Key Genes

Background: Ovarian cancer (OV) is a fatal gynecologic malignancy and has poor survival rate in women over the age of forty. In our study, we aimed to identify genes related to immune microenvironment regulations and explore genes associated with OV prognosis.Methods: The RNA-seq data of GDC TCGA Ovarian Cancer cohort of 376 patients was retrieved from website. Weighted gene co-expression network analysis (WGCNA) and ESTIMATE algorithm were applied to identify the key genes associated with the immune scores. The correlation between key genes and 22 immune cell types were estimated by using CIBERSORT algorithms.Results: WGCNA showed that the pink module was most correlated with the immune score. Seven of 14 key genes (FCRL3, IFNG, KCNA3, LY9, PLA2G2D, THEMIS, and TRAT1) were significantly associated with the OS of OV patients. Correlation analysis showed our key genes positively related to M1 macrophages, CD8 T cells, plasma cells, regulatory T (Treg) cells and activated memory CD4 T cells, and negatively related to naive CD4 T cells, M0 macrophages, activated dendritic cells (DCs) and memory B cells. Kaplan-Meier survival analysis showed that lower abundances of neutrophils and higher abundances of M1 macrophages, plasma cells, T cells gamma delta (γδT) cells and follicular helper T (Tfh) cells predicted better OV prognosis.Conclusion: Forteen key genes related to the immune infiltrating of OV were identified, and seven of them were significantly related to prognosis. These key genes have potential roles in tumor infiltrating immune cells differentiation and proliferation. This study provided potential prognostic markers and immunotherapy targets for OV.

scholarly journals Tumor Infiltrating Lymphocytes and Macrophages Improve Survival in Microsatellite Unstable Colorectal Cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sumana Narayanan ◽  
Tsutomu Kawaguchi ◽  
Xuan Peng ◽  
Qianya Qi ◽  
Song Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Repair ◽  
Immune Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Types ◽  
The Cancer Genome Atlas ◽  
Dna Repair Genes ◽  
M1 Macrophage ◽  
Infiltrating Lymphocytes ◽  
Repair Genes

Abstract Due to the loss of DNA repair mechanisms in colorectal cancer (CRC) with microsatellite instability (MSI), somatic mutations accumulate within DNA; making them more prone to attack by tumor infiltrating lymphocytes (TIL) and macrophages. We hypothesize that MSI-High (MSI-H) patients have favorable survival due to increased tumor immunogenicity. The Cancer Genome Atlas (TCGA) was used to evaluate gene expression from 283 patients with CRC, comparing MSI-H and microsatellite stable (MSS) patients. CIBERSORT algorithm estimated the fraction of immune cell types. We found that low expression of DNA repair genes (MLH1, MLH3, PMS1, PMS2, ATR, PRKDC, ATM, BRCA2) associated with MSI-H. MSI-H was directly associated with Helper T-cells (p = 0.034) and M1 macrophages (p < 0.0001). MSI-H tumors associated with diminished intra-tumoral heterogeneity as well as higher expression of checkpoint molecules PD-1, PD-L1, CTLA4, LAG3 and TIM3 (p < 0.0001). Improved OS was seen in patients with low ATM, PMS2 and MLH3. In the TCGA CRC cohort, decreased expression of DNA repair genes associated with MSI-H. MSI-H patients had improved survival, likely due to higher TIL and M1 macrophage infiltration as well as lower intra-tumoral heterogeneity. MSI-H also associates with expression of immune checkpoint molecules with potential for development of therapeutic targets.

scholarly journals CD4+CD25highCD127low/−FoxP3+ Regulatory T Cell Subpopulations in the Bone Marrow and Peripheral Blood of Children with ALL: Brief Report

2018 ◽  
Vol 2018 ◽  
pp. 1-9
Author(s):  
M. Niedźwiecki ◽  
O. Budziło ◽  
M. Zieliński ◽  
E. Adamkiewicz-Drożyńska ◽  
L. Maciejka-Kembłowska ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Negative Correlation ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Lymphoblastic Leukemia ◽  
Immune Therapy ◽  
Treg Cells ◽  
Small Subset

CD4+CD25highCD127low/−FoxP3+ regulatory T cells (Tregs) are currently under extensive investigation in childhood acute lymphoblastic leukemia (ALL) and in other human cancers. Usually, Treg cells maintain the immune cell homeostasis. This small subset of T cells has been, in fact, considered to be involved in the pathogenesis of autoimmune diseases and progression of acute and chronic leukemias. However, whether Treg dysregulation in CLL and ALL plays a key role or it rather represents a simple epiphenomenon is still a matter of debate. Treg cells have been proposed as a prognostic indicator of the clinical course of the disease and might also be used for targeted immune therapy. Our study revealed statistically higher percentage of Treg cells in the bone marrow than in peripheral blood in the group of 42 children with acute lymphoblastic leukemia. By analyzing Treg subpopulations, it was shown that only memory Tregs in contact with leukemic antigens showed statistically significant differences. We noticed a low negative correlation between Treg cells in the bone marrow and the percentage of blasts (R=−0.36) as well as a moderate correlation between Treg cells in the bone marrow and Hb level (R=+0.41) in peripheral blood before therapy. The number of peripheral blood blasts on day 8th correlates negatively (R=−0.36) with Tregs. Furthermore, statistical analysis revealed low negative correlation between the number of Tregs in the bone marrow and the minimal residual disease measured on day 15th, the percentage of blasts in the bone marrow and leukocytosis after 15 days of chemotherapy. These results indicate the influence of Tregs on the final therapeutic effect.

scholarly journals Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

2021 ◽  
Vol 22 (15) ◽  
pp. 8042
Author(s):  
Mengmeng Jin ◽  
Katja Akgün ◽  
Tjalf Ziemssen ◽  
Markus Kipp ◽  
Rene Günther ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Th17 Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Positive Control ◽  
Interleukin 17 ◽  
Fused In Sarcoma ◽  
Th17 Lymphocytes ◽  
Human Ipscs ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.

747 Evaluation of immune microenvironment of primary lung cancer and synchronous liver metastasis with multispectral imaging system

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A795-A795
Author(s):  
Hyeonbin Cho ◽  
Jae-Hwan Kim ◽  
Ji-Hyun Kim
Keyword(s):  
T Cells ◽  
Liver Metastasis ◽  
Multispectral Imaging ◽  
Immune Cell ◽  
Imaging System ◽  
Cytotoxic T Cells ◽  
Primary Lung Cancer ◽  
Helper T Cells ◽  
Synchronous Liver Metastasis ◽  
Immune Microenvironment

BackgroundCancer immunotherapy (CIT) has substantially improved the survival of cancer patients. However, according to recent studies, liver metastasis was reported to predict worse outcomes for CIT. The main objective of the study is to evaluate the differences in the immune microenvironment (IME) between the primary lung cancer (PL) and synchronous liver metastasis (LM) using a multispectral imaging system.MethodsSix immune markers (CD4, CD8, CTLA-4, granzyme B (GZB), Foxp3 and PD-L1) were analyzed using a multiplex IHC system and inForm program (Akoya) on paired lung-liver samples of 10 patients. Cells were categorized into tumor nest and stroma, and cell counts per unit area were measured for comparison.ResultsThe number of tumor-infiltrating cytotoxic T cells (TIL) in PL (262.5 cells/mm2) was higher than that of LM (113.3 cells/mm2). Additionally, the ratio between the number of TIL and non-TIL was greater in PL (0.31) compared to that of LM (0.26). A similar trend appeared for Helper T cells and regulatory T cells (Treg), as PL consisted of higher numbers of T cells (791.8 Helper T cells/mm2, 195.7 Treg/mm2) than LM (626.3 Helper T cells/mm2, 121.3 Treg/mm2). However, cytotoxic T cells exhibiting GZB+ and CTLA-4- were fewer in PL (140.2 cells/mm2) than in LM (203.3 cells/mm2), and the ratio is 0.69. The mean number of GZB+ TIL in PL (32.5 cells/mm2) was lower than in LM (35.3 cells/mm2), and their proportions among total TIL counts were 0.12 and 0.31, respectively. In PL, GZB+: GZB- ratio is 0.16 while the ratio is 1.91 for LM. A fewer number of TILs exhibiting GZB suggests that PL has lower efficiency in immune response than LM. Another crucial checkpoint receptor that inhibits immune response, CTLA-4, was more prevalent in PL, with CTLA-4+: CTLA-4- ratio in Treg being 0.36 in PL, compared to 0.11 in LM. The tumor proportion score (TPS) of PD-L1 was higher in PL than LM (40.0 vs. 6.6).ConclusionsIn our study, we showed the differences in the numbers of TIL or regulatory T cells and expressions of immune checkpoint receptors (PD-L1, CTLA-4), which significantly influence outcomes for CIT. The study is ongoing to confirm different IME between the PL and LM groups in a larger tumor cohort.ReferencesPeng, Jianhong, et al., Immune Cell Infiltration in the Microenvironment of Liver Oligometastasis from Colorectal Cancer: Intratumoural CD8/CD3 Ratio Is a Valuable Prognostic Index for Patients Undergoing Liver Metastasectomy. Cancers 2019 Dec; 11(12): 1922. https://doi.org/10.3390/cancers11121922Tumeh, Paul C., et al., Liver Metastasis and treatment outcome with Anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res 2017 May; 5(5): 417–424. doi: 10.1158/2326-6066.CIR-16-0325Parra, E.R., Immune Cell Profiling in Cancer Using Multiplex Immunofluorescence and Digital Analysis Approaches; Streckfus, C.F., Ed.; IntechOpen: London, UK, 2018; pp. 1–13. doi: 10.5772/intechopen.80380Ribas, A., Hu-Lieskovan, S., What does PD-L1 positive or negative mean?. The Journal of Experimental Medicine 2016;213(13):2835–2840. https://doi.org/10.1084/jem.20161462

scholarly journals Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Rongqun Guo ◽  
Mengdie Lü ◽  
Fujiao Cao ◽  
Guanghua Wu ◽  
Fengcai Gao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Cell Types ◽  
Developmental Trajectory ◽  
Significant Difference ◽  
Cell Phenotypes ◽  
Acute Myeloid

Abstract Background Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. Methods Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. Results We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. Conclusion Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.

Sign in / Sign up

Export Citation Format

Share Document