Characterization of the impact of daclizumab beta on circulating natural killer cells by mass cytometry

Ranganath, Thanmayi; Simpson, Laura J.; Seiler, Christof; Ferreira, Anne-Maud; Vendrame, Elena; Zhao, Nancy Q.; Fontenot, Jason D.; Holmes, Susan; Blish, Catherine A.

doi:10.1101/865477

Cited by 3 publications

(2 citation statements)

References 43 publications

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“…4). 53 The cyclophosphamide‐mediated inhibition of CCR2‐positive Tregs causes a decline in immunosuppressive effects and an enhancement in CD8‐positive cytotoxic T‐cell activation 54 . Krejcik et al observed that daratumumab treatment caused a decrease in the immune‐suppressive Treg population that expresses CD38 in patients who have cancer, with a concurrent increase in T‐helper and CD8‐positive T cells 55 .…”

Section: Targeting Treg‐mediated Immune Suppression In Bcmentioning

confidence: 99%

Regulatory T cells: Their role in triple‐negative breast cancer progression and metastasis

Malla¹,

Padmaraju²,

Vempati³

et al. 2022

Cancer

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Triple‐negative breast cancer (TNBC) is an aggressive and immunogenic subtype of breast cancer. This tumorigenicity is independent of hormonal or HER2 pathways because of a lack of respective receptor expression. TNBC is extremely prone to drug resistance and early recurrence because of T‐regulatory cell (Treg) infiltration into the tumor microenvironment (TME) in addition to other mechanisms like genomic instability. Tumor‐infiltrating Tregs interact with both tumor and stromal cells as well as extracellular matrix components in the TME and induce an immune‐suppressive phenotype. Hence, treatment of TNBC with conventional therapies remains challenging. Understanding the protective mechanism of Tregs in shielding TNBC from antitumor immune responses in the TME will pave the way for developing novel, immune‐based therapeutics. The current review focuses on the role of tumor‐infiltrating Tregs in tumor progression and metabolic reprogramming of the TME. The authors have extended their focus to oncotargeting Treg‐mediated immune suppression in breast cancer. Because of its potential role in the TME, modulating Treg activity may provide a novel strategic intervention to combat TNBC. Both under laboratory conditions and in clinical trials, currently available anticancer drugs and natural therapeutics as potential agents for targeting Tregs are explored.

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Section: Targeting Treg‐mediated Immune Suppression In Bcmentioning

confidence: 99%

Regulatory T cells: Their role in triple‐negative breast cancer progression and metastasis

Malla¹,

Padmaraju²,

Vempati³

et al. 2022

Cancer

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“…We applied CytoGLMM in wide range of immunology studies: comparison between influenza strains (Kronstad et al 2018), comparison between pregnant and non-pregnant women (Le Gars et al 2019), comparison between healthy controls and HIV+ individuals (Vendrame et al 2020), comparison between multiple sclerosis patients treated with daclizumab beta or placebo (Ranganath et al 2020), and comparison between Beninese sex workers and healthy controls (Zhao et al 2020). Our next step is extending CytoGLMM to include more complicated experimental designs; e.g.…”

Section: Discussionmentioning

confidence: 99%

CytoGLMM: Conditional Differential Analysis for Flow and Mass Cytometry Experiments

Seiler

Ferreira

Kronstad

et al. 2020

Preprint

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BackgroundFlow and mass cytometry are important modern immunology tools for measuring expression levels of multiple proteins on single cells. The goal is to better understand the mechanisms of responses on a single cell basis by studying differential expression of proteins. We focus on cell-specific differential analysis and one fixed cell type. In contrast, most current methods learn cell types and perform differential analysis jointly. Our narrower field of application allows us to define a more specific statistical model with easier to control statistical guarantees.ResultsDifferential analysis of marker expressions can be difficult due to marker correlations and inter-individual heterogeneity, particularly for studies of human immunology. We address these challenges with two multiple regression strategies: A bootstrapped generalized linear model and a generalized linear mixed model. On simulated datasets, we compare the robustness towards marker correlations and heterogeneity of both strategies. For paired experiments, we find that both strategies maintain the target false discovery rate under medium correlations and that mixed models are statistically more powerful under the correct model specification. For unpaired experiments, our results indicate that much larger patient sample sizes are required to detect differences. We illustrate the CytoGLMMR package and workflow for both strategies on a pregnancy dataset.ConclusionsOur approach to find differential proteins in flow and mass cytometry data reduces biases arising from maker correlations and safeguards against false discoveries induced by patient heterogeneity.

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Treg cells maintain selective access to IL-2 and immune homeostasis despite substantially reduced CD25 function

Hayes

Hagan

Campbell

2019

Preprint

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Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its impact on both regulatory T (Treg) and effector T (Teff) cells. However, the precise role of IL-2 in the maintenance and function of Treg cells in the adult peripheral immune system remains unclear.Here, we report that neutralization of IL-2 abrogated all IL-2 receptor signaling in Treg cells, resulting in rapid dendritic cell (DC) activation and subsequent Teff cell proliferation. By contrast, despite substantially reduced IL-2 sensitivity, Treg cells maintained selective IL-2 signaling and prevented immune dysregulation following treatment with the inhibitory anti-CD25 antibody PC61, even when CD25 hi Treg cells were depleted. Thus, even with severely curtailed CD25 expression and function, Treg cells maintain selective access to IL-2 in vivo. Antibody-mediated targeting of CD25 is being actively pursued for treatment of autoimmune disease and preventing allograft rejection, and our findings help inform therapeutic manipulation and design for optimal patient outcomes. Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its role in the development, maintenance and function of T regulatory (Treg) cells and its impact on effector cell proliferation and differentiation [1,2]. The IL-2 receptor can be composed of 2 or 3 subunits: IL-2Rβ (CD122) and the common gamma (γc) chain (CD132) together form the intermediate affinity receptor, and the addition of IL-2Rα (CD25) creates the high affinity receptor. Binding of CD25 to IL-2 induces a conformational change that decreases the energy needed to bind to the rest of the receptor, whereas CD122 and CD132 are the critical signaling chains [3]. Treg cells constitutively express CD25, which under homeostatic conditions allows them to outcompete CD25 -T effector (Teff) cells and natural killer (NK) cells for limiting amounts of IL-2. This is most important in the secondary lymphoid organs (SLOs), where prosurvival signals downstream of IL-2 signaling maintain Treg cells [4,5]. Notably, Treg cells cannot make their own IL-2 [6, 7] and depend on IL-2 produced mainly from autoreactive CD4 + Teff cells [8,9]. In this way, Teff and Treg cell populations are dynamically linked and reciprocally control each other to maintain immune homeostasis [10].When the IL-2-dependent balance of Treg and Teff cells is disrupted, autoimmunity and inflammation can occur. Genetic deficiency in CD25, CD122, or IL-2 results in systemic autoimmune disease in mice [11], and single nucleotide polymorphisms (SNPs) in the IL2 and IL2RA genes are associated with multiple autoimmune diseases in both mice and humans [12,13]. Therefore, manipulating the IL-2 signaling pathway therapeutically for treatment of autoimmune disease is an area of immense interest. Low dose IL-2 therapy, which enriches Treg cells, has shown efficacy in a wide variety of murine autoimmune models [14][15][16][17][18][19], and has also benefitted patients with graft versus host disease (GVHD) [20], Hepatitis C virus-induced vasculitis ...

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Characterization of the impact of daclizumab beta on circulating natural killer cells by mass cytometry

Cited by 3 publications

References 43 publications

Regulatory T cells: Their role in triple‐negative breast cancer progression and metastasis

Regulatory T cells: Their role in triple‐negative breast cancer progression and metastasis

CytoGLMM: Conditional Differential Analysis for Flow and Mass Cytometry Experiments

Treg cells maintain selective access to IL-2 and immune homeostasis despite substantially reduced CD25 function

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