scholarly journals Tumors induce de novo steroid biosynthesis in T cells to evade immunity

2018 ◽  
Author(s):  
Bidesh Mahata ◽  
Jhuma Pramanik ◽  
Louise van der Weyden ◽  
Krzysztof Polanski ◽  
Gozde Kar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
De Novo ◽  
Steroid Biosynthesis ◽  
Genetic Ablation ◽  
Tumor Immunosuppression

ABSTRACTTumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a novel transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway was sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

scholarly journals 641 Spatially organized multicellular immune hubs in MMRd and MMRp colorectal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A670-A670
Author(s):  
Jonathan Chen ◽  
Karin Pelka ◽  
Matan Hofree ◽  
Marios Giannakis ◽  
Genevieve Boland ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Mismatch Repair ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Single Cells ◽  
Large Set ◽  
Colon Tissue

BackgroundImmune responses to cancer are highly variable, with DNA mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. Almost all tumors are infiltrated with immune cells, but the types of immune responses and their effects on tumor growth, metastasis and death, vary greatly between different cancers and individual tumors. Which of the numerous cell subsets in a tumor contribute to the response, how their interactions are regulated, and how they are spatially organized within tumors remains poorly understood.MethodsTo understand the rules governing these varied responses, we transcriptionally profiled 371,223 single cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd treatment-naive patients. We developed a systematic approach to discover cell types, their underlying gene programs, and cellular communities based on single cell RNA-seq (scRNAseq) profiles and applied it to study the distinguishing features of human MMRd and MMRp colorectal cancer. Cellular communities discovered from this analysis were spatially mapped in tissue sections using multiplex RNA in situ hybridization microscopy.ResultsTo understand the basis for differential immune responses in CRC, we first determined and compared the immune cell composition of MMRd and MMRp CRC and normal colon tissue, finding dramatic remodeling between tumor and normal tissue and between MMRd and MMRp tumors, particularly within the myeloid, T cell, and stromal compartments. Among the clusters enriched in MMRd tumors were activated CXCL13+ CD8 T cells. Importantly, gene program co-variation analysis revealed multicellular networks. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated IFNG+ and CXCL13+ T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines (figure 1).ConclusionsOur study provides a rich dataset of cellular states, gene programs and their transformations in tumors across a relatively large cohort of patients with colorectal cancer. Our predictions of several multicellular hubs based on co-variation of gene expression programs, and subsequent spatial localization of two major immune-malignant hubs, organizes a large set of cell states and programs into a smaller number of coordinated networks of cells and processes. Understanding the molecular mechanisms underlying these hubs, and studying their temporal and spatial regulation upon treatment will be critical for advancing cancer therapy.Ethics ApprovalThis study was approved by the DF-HCC institutional review board (protocols 03-189 and 02-240).Abstract 641 Figure 1A coordinated network of CXCL13+ T cells with myeloid and malignant cells expressing ISGs. Image shows a portion of formalin-fixed paraffin-embedded tissue from an MMRd CRC specimen stained with multiplex RNA ISH / IF for PanCK-IF, CD3E-ISH, CXCL10/CXCL11-ISH, CXCL13-ISH, and IFNG-ISH. Note IFNG+ and CXCL13+ cells in proximity to cells expressing the chemokines CXCL10/CXCL11

scholarly journals Intestinal helminth infection transforms the CD4+ T cell composition of the skin

2021 ◽  
Author(s):  
Cajsa H. Classon ◽  
Muzhen Li ◽  
Ada Lerma Clavero ◽  
Junjie Ma ◽  
Xiaogang Feng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Chemokine Receptors ◽  
Immune Cell ◽  
Intestinal Helminth ◽  
Helminth Parasites ◽  
Long Term Effects ◽  
Mesenteric Lymph Nodes ◽  
Cell Composition

AbstractIntestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, implying effects on host immune responses in distal barrier tissues. We herein show that the skin of C57BL/6 mice infected with the strictly intestinal nematode Heligmosomoides polygyrus contain higher numbers of CD4+ T cells compared to the skin of uninfected controls. Accumulated CD4+ T cells were H. polygyrus-specific TH2 cells that skewed the skin CD4+ T cell composition towards a higher TH2/TH1 ratio which persisted after worm expulsion. Accumulation of TH2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4+ T cells in the blood and mesenteric lymph nodes draining the infected intestine and was abolished by FTY720 treatment during infection, indicating gut-to-skin trafficking of cells. Remarkably, skin TH2 accumulation was associated with impaired capacity to initiate IFN-γ recall responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel process for T cell colonisation and worm-mediated immunosuppression in this organ.

Heparin-Induced Thrombocytopenia Is a Thymus (T cell) Dependent Disorder.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3020-3020
Author(s):  
Shayela Suvarna ◽  
Emily K.E. McCracken ◽  
Gowthami M. Arepally
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
De Novo ◽  
Antibody Responses ◽  
Peripheral Tolerance ◽  
Immune Disorder ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Drug Dependent

Abstract Heparin-Induced Thrombocytopenia (HIT) is a drug-dependent immune disorder caused by autoantibodies to Platelet Factor 4 (PF4) and heparin. The immune basis of HIT is poorly understood. Recent studies describing transient antibody responses and absence of immunologic memory in HIT suggest that PF4/heparin autoantibodies may develop independently of T cell help. To investigate the cellular basis of the HIT immune response, we have developed a murine autoimmune model in which anti-murine PF4/heparin (anti-mP+H) arise de novo. Cohorts of BALB/c mice were immunized daily either intravenously (IV, n=10) or intraperitoneally (IP, n=10) for five days with complexes of murine (m) PF4/heparin (IV, n=5 or IP, n=5), heparin alone (IV, n= 2) or buffer (IV, n=3 or IP, n=5). Mice were screened for anti-mP+H for four weeks after immunization using a murine PF4/heparin ELISA. Peak antibody responses to antigen were seen at 11–15 days in 2/5 mice injected with IV mP+H (Day 11, mouse IV P+H #0 peak A450nm =0.34±0.01; Day15 mouse IV P+H #2 peak A450nm =0.69±0.01), and at days 22–25 in 2/5 mice injected by IP route (Day 22, mouse IP P+H #0 peak A450nm =0.37±0.01; Day 25 mouse IP P+H #2 peak A450nm =0.78±0.02). Anti-mP+H were not detected in mice injected with heparin alone or buffer alone at any time point (peak maximum IV A450nm= 0.1±0.001, Control #2; mouse IP P+H Control #2 A450nm =0.04±0.002). Serologically, murine autoantibodies were similar to anti-human (h) PF4/heparin. Anti-mP+H reactivity was specific for murine antigen (mouse IV P+H #2 A450nm=0.65±0.06), and was reduced with antigen in the presence of excess heparin (A450nm=0.38±0.01). Minimal reactivity was seen with wells coated with hP+H (A450nm=0.09±0.005), albumin (mouse IV P+H #2 A450nm=0.15±0.03), or PBS alone (mouse IV P+H #2 A450nm =0.16±0.01). Similar to human HIT antibodies, anti-mP+H were of IgG1 subclass. To determine if T cells are required for development of anti-mP+H, mice lacking T cell function (BIG:BALB/c-Nu, n=10) were injected IV with mP+H daily for five days. Unlike euthymic mice, nude mice did not manifest any antibody responses to IV injections of mP+H. In summary, we have developed a novel murine autoimmune model of anti-PF4/heparin that recapitulates many salient features of the human immune syndrome. Using this murine model, we demonstrate that T cells are essential for development PF4/heparin autoantibodies. Studies are currently underway to delineate mechanisms of T cell regulation and peripheral tolerance in HIT.

scholarly journals Intestinal helminth infection transforms the CD4+ T cell composition of the skin

2021 ◽  
Author(s):  
Cajsa Helena Classon ◽  
Muzhen Li ◽  
Junjie Ma ◽  
Ada Lerma Clavero ◽  
Xiaogang Feng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Th2 Cells ◽  
Intestinal Helminth ◽  
Long Term Effects ◽  
Cell Composition

Intestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, indicating effects on host immune responses in distal barrier tissues. We herein show that C57BL/6 mice infected with the strictly intestinal nematode Heligmosomoides polygyrus have impaired capacity to initiate skin immune responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. Surprisingly, and in contrast to a previously noted loss of T cells in peripheral lymph nodes, the skin of worm-infected mice harboured higher numbers of CD4+ T cells compared to skin of uninfected controls. H. polygyrus-specific TH2 cells accumulated during infection and remained after worm expulsion. Accumulation of TH2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4+ T cells in blood and mesenteric lymph nodes draining intestinal tissues, indicating gut-to-skin trafficking of cells. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel mechanism for T cell colonization and worm-mediated immunosuppression in this organ.

scholarly journals Conclusive Identification of Senescent T Cells Reveals Their Abundance in Aging Humans

2020 ◽  
Author(s):  
Ricardo Iván Martínez-Zamudio ◽  
Hannah K. Dewald ◽  
Themistoklis Vasilopoulos ◽  
Lisa Gittens-Williams ◽  
Patricia Fitzgerald-Bocarsly ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Function ◽  
Immune Cell ◽  
Functional Decline ◽  
The Elderly ◽  
Cd8 T Cell ◽  
Cell Senescence ◽  
Healthy Humans

ABSTRACTAging leads to a progressive functional decline of the immune system, which renders the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this functional decline, however, remains unclear since methods to accurately identify and isolate senescent immune cells are missing. By measuring senescence-associated ß-galactosidase activity, a hallmark of senescent cells, we demonstrate here that healthy humans develop senescent T lymphocytes in peripheral blood with advancing age. Particularly senescent CD8+ T cells increased in abundance with age, ranging from 30% of the total CD8+ T cell population in donors in their 20s and reaching levels of 64% in donors in their 60s. Senescent CD8+ T cell populations displayed features of telomere dysfunction-induced senescence as well as p16-mediated senescence, developed in various T cell differentiation states and established gene expression signatures consistent with the senescence state observed in other cell types. On the basis of our results we propose that cellular senescence of T lymphocytes is a major contributing factor to the observed decline of immune cell function with advancing age and that immune cell senescence, therefore, plays a significant role in the increased susceptibility of the elderly to age-associated diseases and infection.

scholarly journals Immune deconvolution and temporal mapping identifies stromal targets and developmental intervals for abrogating murine low-grade optic glioma formation

2021 ◽  
Author(s):  
Amanda de Andrade Costa ◽  
Jit Chatterjee ◽  
Olivia Cobb ◽  
Elizabeth Cordell ◽  
Astoria Chao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Tumor Formation ◽  
Optic Glioma ◽  
Low Grade ◽  
Dependent Manner ◽  
Cancer Predisposition Syndrome

Abstract Background Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1-OPG murine models, we previously demonstrated that murine Nf1-OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo. While these interactions are critical for established Nf1-OPG tumor growth, their importance in tumor formation has not been explored. Methods A combination of bulk and single cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments. Results We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8 + T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor (Ccr4) expression in CD8 +, but not CD4 +, T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3-6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment. Conclusions Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation.

scholarly journals Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Nicole V. Acuff ◽  
Xin Li ◽  
Krishna Latha ◽  
Tamas Nagy ◽  
Wendy T. Watford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cd4 T Cell ◽  
Citrobacter Rodentium ◽  
Wild Type ◽  
Content Type ◽  
Cell Recruitment ◽  
Ifn Γ

ABSTRACT Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-γ), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 −/− mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 −/− mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-γ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag −/− mice, Tpl2 −/− CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 −/− mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function.

scholarly journals Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months

2015 ◽  
Vol 114 (6) ◽  
pp. 891-898 ◽  
Author(s):  
Magdalena Muc ◽  
Eskil Kreiner-Møller ◽  
Jeppe M. Larsen ◽  
Sune Birch ◽  
Susanne Brix ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
T Cell ◽  
Breast Milk ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Ex Vivo ◽  
Fatty Acid Desaturase ◽  
Cell Counts

AbstractBreast milk long-chain PUFA (LCPUFA) have been associated with changes in early life immune responses and may modulate T-cell function in infancy. We studied the effect of maternal fatty acid desaturase (FADS) genotype and breast milk LCPUFA levels on infants’ blood T-cell profiles and ex vivo-produced cytokines after anti-CD3/CD28 stimulation of peripheral blood mononuclear cells in 6-month-old infants from the Copenhagen Prospective Study of Asthma in Childhood birth cohort. LCPUFA concentrations of breast milk were assessed at 4 weeks of age, and FADS SNP were determined in both mothers and infants (n 109). In general, breast milk arachidonic acid (AA) levels were inversely correlated with the production of IL-10 (r −0·25; P=0·004), IL-17 (r −0·24; P=0·005), IL-5 (r −0·21; P=0·014) and IL-13 (r −0·17; P=0·047), whereas EPA was positively correlated with the counts of blood regulatory T-cells and cytotoxic T-cells and decreased T-helper cell counts. The minor FADS alleles were associated with lower breast milk AA and EPA, and infants of mothers carrying the minor allele of FADS SNP rs174556 had higher production of IL-10 (r −0·23; P=0·018), IL-17 (r −0·25; P=0·009) and IL-5 (r −0·21; P=0·038) from ex vivo-activated immune cells. We observed no association between T-cell distribution and maternal or infant FADS gene variants. We conclude that increased maternal LCPUFA synthesis and breast milk AA are associated with decreased levels of IL-5, IL-13 (type-2 related), IL-17 (type-17 related) and IL-10 (regulatory immune responses), but not with interferon-γ and TNF-α, which could be due to an effect of the maternal FADS variants on the offspring immune response transferred via breast milk LCPUFA.

Immunologic impact of anti-CTLA-4 therapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3019-3019
Author(s):  
P. Sharma ◽  
D. Tsavachidou ◽  
A. Kamat ◽  
D. Ng Tang ◽  
H. Chen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Metastatic Disease ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Systemic Circulation ◽  
Tumor Tissues

3019 Background: Blockade of the T-cell inhibitory molecule known as cytotoxic T lymphocyte antigen-4 (CTLA-4) results in antitumor responses. To date, trials have been conducted with over 4,000 patients with various malignancies in the metastatic disease setting, which allow for correlation of therapy with clinical outcome but do not provide analyses of relevant biomarkers in the systemic circulation that reflect changes within the tumor microenvironment. Approximately 10% of treated patients respond to therapy. Why some patients respond while others do not remains unknown. The identification of intermediate biomarkers are essential for us to understand whether anti-CTLA-4 antibody has “hit its target” to affect human immune responses and whether these identified immune responses can serve as predictive markers of clinical outcomes. Methods: We conducted a presurgical clinical trial with anti-CTLA-4 antibody. Patients with localized bladder cancer (N=10) were given two doses of antibody prior to undergoing surgery. Immunological analyses were conducted on patients’ tissues and blood samples. Results: Expression of the inducible costimulator (ICOS) molecule was increased on CD4 T cells within tumor tissues and systemic circulation. ICOS-expressing T-cells have not previously been reported to have a role in anti-tumor responses. We showed that CD4+ICOShi T cells produced IFNγ and could recognize the NY-ESO-1 tumor antigen. Pre- and post-therapy CD4 T cells were analyzed by reverse-phase protein array and microRNA array, which led to the identification of signaling pathways and regulatory mechanisms that play a role in enhanced T-cell function. Furthermore, murine models confirmed our initial findings and implied a role for ICOS-expressing T-cells in antitumor responses. Finally, we extended our findings to the metastatic disease setting of melanoma patients (N=14) and our preliminary data indicate an improved survival for anti-CTLA-4 treated patients who have a sustained increase in ICOS-expressing CD4 T cells. Conclusions: Our presurgical clinical trial allowed for the correlation of data from tumor tissues with data from peripheral blood, thus identifying ICOS-expressing T-cells as a relevant biomarker that can be used to monitor patients who receive anti-CTLA-4 therapy. [Table: see text]

scholarly journals Nanoengineering of Immune Cell Function

2009 ◽  
Vol 1209 ◽  
Author(s):  
Keyue Shen ◽  
Michael C Milone ◽  
Michael L. Dustin ◽  
Lance Cameron Kam
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Cell Communication ◽  
Cell Therapies ◽  
Nano Scale

AbstractT lymphocytes are a key regulatory component of the adaptive immune system. Understanding how the micro- and nano-scale details of the extracellular environment influence T cell activation may have wide impact on the use of T cells for therapeutic purposes. In this article, we examine how the micro- and nano-scale presentation of ligands to cell surface receptors, including microscale organization and nanoscale mobility, influences the activation of T cells. We extend these studies to include the role of cell-generated forces, and the rigidity of the microenvironment, on T cell activation. These approaches enable delivery of defined signals to T cells, a step toward understanding the cell-cell communication in the immune system, and developing micro/nano- and material- engineered systems for tailoring immune responses for adoptive T cell therapies.

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