scholarly journals Patterns of TIGIT Expression in Lymphatic Tissue, Inflammation, and Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Niclas C. Blessin ◽  
Ronald Simon ◽  
Martina Kluth ◽  
Kristine Fischer ◽  
Claudia Hube-Magg ◽  
...  
Keyword(s):  
T Cells ◽  
Checkpoint Inhibitors ◽  
Inflammatory Diseases ◽  
Cytotoxic T Cells ◽  
Tissue Microarrays ◽  
Cell Types ◽  
Hashimoto Thyroiditis ◽  
Lung Cancers ◽  
Variable Expression ◽  
Tissue Compartments

TIGIT is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. Here, we analysed two different types of tissue microarrays of healthy lymphatic and various inflamed tissues, colorectal and lung cancers, as well as >1700 tumour samples from 86 different tumour entities for TIGIT and/or PD-1 by bright field and/or multiplex fluorescence immunohistochemistry. TIGIT was detected in CD8+ cytotoxic T cells, CD4+ T helper cells, FOXP3+ regulatory T cells, and NK cells, but not in CD11c+ dendritic cells, CD68+ macrophages, and CD20+ B lymphocytes. TIGIT expression paralleled that of PD-1. More than 70% of TIGIT+ cells were PD-1+, and more than 90% of the PD-1+ cells were TIGIT+. Expression varied between different tissue compartments. TIGIT expression in tonsil gradually increased from the interfollicular area over the marginal/mantle zone to the germinal centre in all T cell subtypes. In inflammatory diseases, the strongest expression of TIGIT/PD-1 was found in Hashimoto thyroiditis. TIGIT+ lymphocytes were seen in all 86 different tumour entities with considerable high variability of TIGIT positivity within and between different cancer entities. Particularly, high densities of TIGIT+ lymphocytes were, for example, seen in squamous cell cancers of various origins. In summary, the variable expression levels of TIGIT and PD-1 in cell types and tissue compartments illustrate the high complexity of immune microenvironments. The high frequency of TIGIT (and PD-1) expressing lymphocytes in cancers highlights considerable opportunities for cotargeting with checkpoint inhibitors.

scholarly journals P03.06 Pattern of Ki67+expanding CD8+cytotoxic T cells in healthy tissues, inflammation and the cancer microenvironment

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A24.2-A25
Author(s):  
K Möller ◽  
M Lennartz ◽  
R Abu-Hashem ◽  
NC Blessin ◽  
T Mandelkow ◽  
...  
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Microsatellite Instability ◽  
Inflammatory Diseases ◽  
Cytotoxic T Cells ◽  
Lichen Sclerosus ◽  
Tissue Microarrays ◽  
Hashimoto Thyroiditis ◽  
Lymphoid Tissues

BackgroundExpansion of CD8+ cytotoxic T lymphocytes is a prerequisite for anti-cancer immune activity. In the era of immune checkpoint therapy, profound knowledge of the dynamics of CD8+ has regained considerable interest. However, systematically acquired data on CD8+ proliferation in large sets of normal and diseased tissues are sparse.Materials and MethodsHere, we applied multiplex fluorescence immunohistochemistry to conventional large sections and tissue microarrays in order to quantitate Ki67+CD8+ cells in >20 different compartments of normal lymphoid tissues, 7 types of inflammatory diseases and 785 cancers.ResultsIn most normal lymphoid tissues (tonsil, lymph node, thymus, Peyer’s patches, spleen, colon, appendix) the percentage of Ki67+CD8+ cells typically did not exceed 3%. The percentage of Ki67+CD8+ cells was markedly higher (45%) in the immune-active cortex of the thymus, however. In inflammatory conditions (including Hashimoto thyroiditis, Lichen sclerosus of the penis, sarcoidosis, sialadenitis, IgG4 pancreatitis, Crohn’s disease and eczema), the percentage of Ki67+CD8+ cells was much more variable and often sharply higher than in normal tissues. It ranged from 0.5% in one patient with sialadenitis to 19% in the intraepithelial compartment of Crohn’s disease. In 765 colorectal cancers, the fraction of Ki67 positive CD8+ cytotoxic T cells ranged from 0 to 100% (mean: 20.6%). A high fraction of Ki67+CD8+ cells was significantly associated with microsatellite instability (p<0.0001), low pT stage (p<0.0001) and absence of nodal metastases (p=0.0005).ConclusionsIn summary, our data show a variable increase of the fraction of proliferating CD8+ T cells in cancers and in inflammatory diseases as compared to healthy secondary lymphoid organs. The striking link with microsatellite instability and unfavorable tumor features suggest a potential clinical utility of assessing Ki67+CD8+ in colorectal cancer.Disclosure InformationK. Möller: None. M. Lennartz: None. R. Abu-Hashem: None. N.C. Blessin: None. T. Mandelkow: None. E. Bady: None. C. Hube-Magg: None. R. Simon: None. G. Sauter: None. C. Fraune: None. T.S. Clauditz: None. F. Büscheck: None. A.M. Luebke: None.

Structure and functions of T-cell immunoglobulin-domain and mucin- domain protein 3 in cancer

2021 ◽  
Vol 28 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Intracellular Signaling ◽  
Checkpoint Inhibitors ◽  
Cell Types ◽  
Structural Features ◽  
Type I ◽  
Potential Biomarker ◽  
Tim Proteins

Background: T-cell immunoglobulin (Ig)-domain and mucin-domain (TIM) proteins represent a family of receptors expressed on T-cells that play essential cellular immunity roles. The TIM proteins span across the membrane belonging to type I transmembrane proteins. The N terminus contains an Ig-like V-type domain and a Ser/Thr-rich mucin stalk as a co-inhibitory receptor. The C-terminal tail oriented toward the cytosol predominantly mediates intracellular signaling. Methods: This review discusses the structural features and functions of TIM-3, specifically on its role in mediating immune responses in different cell types, and the rationale for TIM-3-targeted cancer immunotherapy. Results: TIM-3 has gained significant importance to be a potential biomarker in cancer immunotherapy. It has been shown that blockade with checkpoint inhibitors promotes anti-tumor immunity and inhibits tumor growth in several preclinical tumor models. Conclusion: TIM-3 is an immune regulating molecule expressed on several cell types, including IFNγ-producing T-cells, FoxP3+ Treg cells, and innate immune cells. The roles of TIM-3 in immunosuppression support its merit as a target for cancer immunotherapy.

scholarly journals Identification of RORg+T Cells as Key Players in Thyroid Autoimmunity From Checkpoint Immunotherapy

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A839-A840
Author(s):  
Melissa G Lechner ◽  
Natalie Yakobian ◽  
Anushi Patel ◽  
Eduardo Rodriguez ◽  
Trevor E Angell ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Autoimmune Disease ◽  
Mouse Model ◽  
Checkpoint Inhibitors ◽  
Thyroid Autoimmunity ◽  
Single Agent ◽  
Hashimoto Thyroiditis ◽  
Lymphoid Tissues ◽  
Tc17 Cells

Abstract Purpose: Immune checkpoint inhibitors (ICI) are powerful new cancer therapies that leverage the body’s own immune system to attack cancer cells. Unfortunately, their use may be limited by the development of immune-related adverse events (IrAE) in up to 60% of patients. Thyroiditis is a common IrAE, with shared and distinct features from spontaneous thyroid autoimmunity, i.e. Hashimoto thyroiditis (HT). The cause of IrAE remains unknown, however, recent data suggest that toxicity can be uncoupled from anti-tumor effects. Methods: We developed a novel mouse model to study mechanisms of IrAE, in which ICI (anti-PD-1 and/or anti-CTLA-4) treatment leads to multi-organ immune infiltrates, including thyroiditis. To understand immune changes occurring with ICI-autoimmunity, we first evaluated changes in the frequency and activation status of different immune cells in our mice using immunohistochemistry (IHC) and flow cytometry. Then we confirmed these findings in peripheral blood and thyroid fine needle aspiration (FNA) specimens from patients with ICI-thyroiditis, HT, or no IrAE, using flow cytometry and single cell RNA sequencing (scRNAseq) techniques. Results: In our mouse model, ICI treatment of autoimmune-prone non-obese diabetic mice induces multi-organ autoimmunity. Modeling ICI-IrAE observed in humans, our mice developed increased immune infiltrates in multiple tissues (e.g. thyroid, colon, liver, lung), autoantibodies, and acceleration of underlying autoimmune risk (i.e. diabetes). Increased frequency of autoimmune disease was seen with combination (anti-PD-1 + anti-CTLA-4) vs. single agent ICI. We found increased IL-17A+ T cells in secondary lymphoid tissues of ICI-treated mice, a cytokine produced by RORγ + Th17 and Tc17 cells and associated with autoimmunity. IHC studies on thyroid infiltrates showed accumulation of CD4+ and CD8+ T cells and macrophages in ICI-treated vs. isotype control mice. This finding was confirmed by flow cytometry analyses of thyroid-infiltrating leukocytes in ICI-thyroiditis mice, which showed significantly increased T cells, specifically RORγ + T cells, and rare B220+ B, CD11b+ myeloid, or NKp46+ NK cells. In patients with ICI-thyroiditis, thyroid FNA showed that thyroid immune infiltrates were predominately T cells. scRNAseq studies in patients with ICI-thyroiditis showed enrichment of Th17 and Tc17 (RORγ + IL23R+ CD161+) T cells, compared to ICI-treated patients without IrAE. Conclusion: We have identified a role for RORγ + Th17 and Tc17 cells in thyroid autoimmunity from ICI using a newly developed mouse model of ICI-associated IrAE and translational studies in patients with ICI-thyroiditis. Th17 and Tc17 cells have previously been associated with spontaneous autoimmune disease, including HT, but have not yet been characterized in IrAE. These cells provide a potential therapeutic target for prevention of endocrine IrAE from ICI.

scholarly journals Next-Generation Immunotherapies to Improve Anticancer Immunity

2021 ◽  
Vol 11 ◽  
Author(s):  
Yaoyao Shi ◽  
Katarzyna Tomczak ◽  
June Li ◽  
Joshua K. Ochieng ◽  
Younghee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Cell Subset ◽  
Cytotoxic T Cell ◽  
Killer Cells

Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell–mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.

A study of the immune infiltrate and patient outcomes in esophageal cancer

2020 ◽  
Author(s):  
Melissa J Conroy ◽  
Susan A Kennedy ◽  
Suzanne L Doyle ◽  
Brian Hayes ◽  
Maria Kavanagh ◽  
...  
Keyword(s):  
T Cells ◽  
Esophageal Cancer ◽  
Patient Outcomes ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Tissue Microarrays ◽  
Stromal Compartment ◽  
Cancer Subtypes ◽  
Cd8 Cells ◽  
Esophageal Tumors

Abstract Objectives Cancer patient outcomes and selection for novel therapies are heavily influenced by the immune contexture of the tumor microenvironment. Esophageal cancer is associated with poor outcomes. In contrast to colorectal cancer, where the immunoscore is increasingly used in prognostic staging, little is known about the immune cell populations in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (SCC), and their clinical significance. Methods Tissue microarrays were constructed from resected tumor tissue of 72 EAC patients and 23 SCC patients. Immunohistochemical staining of CD3, CD8, CD56, CD68, CD45RO, CD69, IFN-γ, IL-10, IL-4, IL-17, TGF-β, FOXP3 and CD107a was performed. Positivity was examined in both the stromal and epithelial compartments. Statistical analysis was performed to identify differences in immune cell infiltration and functional phenotypes between cancer subtypes and tissue compartments. Results This study identified that esophageal tumors are enriched with CD45RO+ and CD8+ cells and such positivity is significantly higher in SCC compared with EAC. Furthermore, the expression of CD45RO positively correlates with that of CD8 within the tumors of both patient cohorts, suggesting a dominance of memory cytotoxic T cells. This is supported by strong positivity of degranulation marker CD107a in the stromal compartment of EAC and SCC tumors. Cytokine staining revealed a mixed pro- and anti-inflammatory profile within EAC tumors. Conclusions Esophageal tumors are enriched with memory cytotoxic T cells. Applying these measurements to a larger cohort will ascertain the clinical utility of assessing specific lymphocyte infiltrates in EAC and SCC tumors with regards to future immunotherapy use, patient prognosis and outcomes.

Inhibitory Effect of PD-1/PD-L1 and Blockade Immunotherapy in Leukemia

2021 ◽  
Vol 24 ◽  
Author(s):  
Kai Xing ◽  
Pan Zhou ◽  
Jiaojiao Li ◽  
Miao Liu ◽  
Wei Emma Zhang
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Solid Tumors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Inhibitory Effect ◽  
Main Body ◽  
Intracellular Signals ◽  
Effect Of Pd

Background: PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of a variety of solid tumors. And some clinical trials have also confirmed the excellent efficacy of PD-1/PD-L1 inhibitors on lymphoma. However, the efficacy of PD-1/PD-L1 inhibitors on leukemia remains unclear. Main body: To understand the connection between PD-1/PD-L1 and leukemia better, this review concentrates on the up-regulated expression of PD-1/PD-L1 and the PD-1/PD-L1 blockade trials in participants with leukemia. PD-1/PD-L1 signal performs momentously negative immunoregulation of cancer, which can inhibit the activation of cytotoxic T cells and involve in the immune escape in tumors. Activated PD-1/PD-L1 may transduce negative intracellular signals to block the mitotic cycle and the development of T-cells. Several pathways are involved in these critical biochemical processes, including MAPK, Calcium, PI3K/AKT, and so on. Lately, PD-1/PD-L1 antibodies have illustrated unprecedented curative effects in the field of Hodgkin's lymphoma and some solid tumors. Specimens from patients with leukemia demonstrated the elevated level of PD-1/PD-L1 in T lymphocytes. This finding inspired hematologists to use PD-1/PD-L1 inhibitors for subjects suffering from leukemia. Some clinical trials implied that PD-1/PD-L1 inhibitors could help patients fight against leukemia. However, other researchers reported the opposite results. Conclusions: PD-1/PD-L1 is upregulated in leukemia, but the results regarding PD-1/PD-L1 blockade are mixed and more clinical trials are needed to be conducted.

Characterization of Tumor-immune Microenvironment by High-throughput Image Analysis of CD8 Immunohistochemistry Combined With Modified Masson’s Trichrome

2021 ◽  
pp. 002215542110349
Author(s):  
Charles Havnar ◽  
Shari Lau ◽  
Jeffrey Hung ◽  
Jeff Eastham-Anderson ◽  
Carmina Espiritu ◽  
...  
Keyword(s):  
T Cells ◽  
High Throughput ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Mouse Tissue ◽  
Flexible Tool ◽  
Tissue Samples ◽  
Automated Method ◽  
Tumor Immune Microenvironment ◽  
Tumor Microenviroment

With the advent of checkpoint inhibitors, there is increasing need to study the dynamics of CD8+ T-cells in the tumor microenviroment. In this article, we describe a semi-automated method to quantify and interrogate spatial relationships between T-cells and collagenous stroma in human and mouse tissue samples. The assay combines CD8 immunohistochemistry with modified Masson’s trichrome. Slides are scanned and digital images are analyzed using an adjustable MATLAB algorithm, allowing for high-throughput quantification of cytotoxic T-cells and collagen. This method provides a flexible tool for unbiased quantification of T-cells and their interactions with tumor cells and tumor microenvironment in tissue samples.

scholarly journals RhoA and Cdc42 in T cells: Are they targetable for T cell-mediated inflammatory diseases?

2021 ◽  
Author(s):  
Fukun Guo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Airway Inflammation ◽  
Inflammatory Diseases ◽  
Gene Knockout ◽  
Allergic Airway Inflammation ◽  
Cell Types ◽  
Small Gtpases ◽  
Cellular Functions ◽  
Biological Targets

Abstract Many inflammatory diseases are not curable, necessitating a better understanding of their pathobiology that may help identify novel biological targets. RhoA and Cdc42 of Rho family small GTPases regulate a variety of cellular functions such as actin cytoskeletal organization, cell adhesion, migration, proliferation, and survival. Recent characterization of mouse models of conditional gene knockout of RhoA and Cdc42 has revealed their physiological and cell type-specific roles in a number of cell types. In T lymphocytes, which play an important role in the pathogenesis of most, if not all, of the inflammatory diseases, we and others have investigated the effects of T cell-specific knockout of RhoA and Cdc42 on T cell development in the thymus, peripheral T cell homeostasis, activation, and differentiation to effector and regulatory T cells, and on T cell-mediated allergic airway inflammation and colitis. Here we highlight the phenotypes resulting from RhoA and Cdc42 deletion in T cells and discuss whether pharmacological targeting of RhoA and Cdc42 is feasible in treating asthma that is driven by allergic airway inflammation and colitis.

scholarly journals Titan Cells and Yeast Forms of Cryptococcus neoformans and Cryptococcus gattii Are Recognized by GXMR-CAR

2021 ◽  
Vol 9 (9) ◽  
pp. 1886
Author(s):  
Matheus Henrique dos Santos ◽  
Michele Procópio Machado ◽  
Pappanaicken R. Kumaresan ◽  
Thiago Aparecido da Silva
Keyword(s):  
T Cells ◽  
Cryptococcus Neoformans ◽  
Cytotoxic T Cells ◽  
Fungal Spores ◽  
Cell Types ◽  
Cryptococcus Gattii ◽  
Jurkat Cells ◽  
Single Chain ◽  
Cryptococcus Spp ◽  
Polysaccharide Capsules

Cryptococcosis, a systemic mycosis that affects both the immunocompromised and immunocompetent, is caused by the inhalation of dehydrated yeasts or fungal spores of Cryptococcus gattii or Cryptococcus neoformans. The Cryptococcus spp. polysaccharide capsule is composed mainly of glucuronoxylomannan—GXM, its major virulence factor. The capsule thickness increases to more than 15 μm during titanization, favoring the pathogenesis of cryptococcosis. Previous studies demonstrated that cytotoxic T cells that had been bioengineered with GXM-targeting chimeric antigen receptor (GXMR-CAR) were able to recognize C. neoformans by promoting the control of titanization. GXMR-CAR, a second-generation CAR, contains a single-chain variable fragment that originates from a 18B7 clone: a human IgG4 hinge, followed by a human CD28 (transmembrane/cytoplasmic domains) and a CD3ς chain. In the current study, we redirected T cells to target distinct C. neoformans and C. gattii cell types by GXMR-CAR. Lentiviral particles carrying the GXMR-CAR sequence were used to transduce Jurkat cells, and these modified cells interacted with the GXM of the C. gattii R265 strain. Moreover, GXMR-CAR mediated the recognition of C. gattii and C. neoformans yeasts with both thin and thick polysaccharide capsules, and GXMR-CAR Jurkat cells interacted with titan cells sourced from both Cryptococcus spp. Thus, bioengineered cells using CAR can improve the treatment of cryptococcosis.

scholarly journals Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Kari A. Shaver ◽  
Tayler J. Croom-Perez ◽  
Alicja J. Copik
Keyword(s):  
T Cells ◽  
Immune System ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Current Evidence ◽  
Cell Therapies

Cancer immunotherapy is a highly successful and rapidly evolving treatment modality that works by augmenting the body’s own immune system. While various immune stimulation strategies such as PD-1/PD-L1 or CTLA-4 checkpoint blockade result in robust responses, even in patients with advanced cancers, the overall response rate is low. While immune checkpoint inhibitors are known to enhance cytotoxic T cells’ antitumor response, current evidence suggests that immune responses independent of cytotoxic T cells, such as Natural Killer (NK) cells, play crucial role in the efficacy of immunotherapeutic interventions. NK cells hold a distinct role in potentiating the innate immune response and activating the adaptive immune system. This review highlights the importance of the early actions of the NK cell response and the pivotal role NK cells hold in priming the immune system and setting the stage for successful response to cancer immunotherapy. Yet, in many patients the NK cell compartment is compromised thus lowering the chances of successful outcomes of many immunotherapies. An overview of mechanisms that can drive NK cell dysfunction and hinder immunotherapy success is provided. Rather than relying on the likely dysfunctional endogenous NK cells to work with immunotherapies, adoptive allogeneic NK cell therapies provide a viable solution to increase response to immunotherapies. This review highlights the advances made in development of NK cell therapeutics for clinical application with evidence supporting their combinatorial application with other immune-oncology approaches to improve outcomes of immunotherapies.

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