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Deciphering the Interplay of Regulatory T Cells and the Gut Microbiota in the Regulation of Myeloid Leukemia Stem Cells

Applicant Riether Carsten
Number 179394
Funding scheme Project funding (Div. I-III)
Research institution Medizinische Onkologie Department for BioMedical Research Universität Bern
Institution of higher education University of Berne - BE
Main discipline Experimental Cancer Research
Start/End 01.05.2018 - 30.04.2022
Approved amount 663'406.00
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Keywords (3)

Gut microbiota; Regulatory T cells; Leukemia stem cells

Lay Summary (German)

Lead
Interaktion von Leukämie-Stammzellen mit der Darmflora und regulatorischen T Zellen
Lay summary
Leukämien haben ihren Ursprung in der sogenannten Leukämie-Stammzelle. Diese Stammzellen sind resistent gegen die meisten Therapieansätze wie Chemo- und auch Strahlentherapie und auch gegen die Eliminierung durch das Immunsystem. Eine Heilung der Leukämie kann somit nur mittels kompletter Eliminierung der Leukämie-Stammzelle erfolgen. Resistenzen werden auch durch Interaktionen der Leukämie-Stammzelle mit anderen Zellen aus der Knochenmarksnische ausgebildet. In der Leukämie verändert sich diese Knochenmarksnische u.a. durch die Anhäufung von regulatorischen T Zellen. Wir haben in ersten Experimenten herausgefunden, das regulatorische T Zellen in der Leukämie im Knochenmark vermehrt sind mit dem Vorschreiten der Krankheit weiter anhäufen. Außerdem konnten wir zeigen, dass keimfreie-Mäuse vor einer Leukämie geschützt sind und dass dieser Schutz abhängig ist von regulatorischen T Zellen. In dieser Studie werden wir nun das komplexe Zusammenspiel zwischen regulatorischen T Zellen, Darmflora und Leukämie-Stammzellen untersuchen. Ziel ist es Mechanismen zu identifizieren und Therapieansätze zu entwickeln, die die Darmflora oder regulatorischen T Zellen so verändern, dass Leukämie-Stammzellen eliminiert werden.
Direct link to Lay Summary Last update: 09.04.2018

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Associated projects

Number Title Start Funding scheme
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP

Abstract

Leukemia stem cells (LSCs) are the origin of any myeloid leukemia and are thought to reside at the top of the leukemic hierarchy, like hematopoietic stem cells (HSCs) in hematopoiesis. LSCs are often resistant against standard treatment and against immune control due to various escape mechanisms and therefore represent a major obstacle for the cure of leukemia. This resistance is partially mediated by protective mechanisms of the HSC niche including immune cells in the bone marrow (BM) in which these LSCs reside. In leukemia, the BM microenvironment changes dramatically inter alia with regulatory T cells (Tregs) accumulating. However, little is known about the mechanisms that regulate these changes in the BM and lead to an immunosuppressive environment. The aim of this proposal is to determine the as yet unanticipated role of Tregs on LSCs, and thereby identify novel immunotherapeutic mechanisms to re-direct the body’s immune system against LSCs. The proposed work provides a link between my recent work on immune control of LSCs, and our novel findings that (a) numbers/frequencies of Tregs are significantly increased and correlate with leukemia load in the BM, that (b) germ-free (GF) mice are resistant against experimental leukemia induction and that (c) this resistance of GF mice depends on Tregs. As the gut flora critically regulates the development of Tregs, I hypothesize the gut flora is an important driver of Treg accumulation and immunosuppression in leukemia. I propose a multidisciplinary approach combining immunology, hematology and gastroenterology to address the subsequent aims: 1.To investigate the mechanisms by which Tregs in the BM accumulate and regulate LSC function in mice and humans. The role of Tregs in murine CML and AML will be analyzed in FoxP3DTR-GFP mice. Leukemia development, LSC numbers and function will be determined in vitro and in serial-transplantation experiments in vivo. Treg phenotype and function will be analyzed in BM and spleen of leukemia mice. The extrapolation of these findings towards human leukemia will be evaluated by lentiviral overexpression or silencing of identified targets in Tregs from newly diagnosed CML/AML patients and by correlation analysis of Treg phenotype and function with clinical endpoints and parameters.2.To characterize the molecular signature of Tregs in leukemia patients to define targets for immunotherapy. The expression profile of FACS-purified activated and resting Tregs (aTregs and rTregs) from BM and blood of newly diagnosed AML patients from our leukemia biobank (>150 AML samples at diagnosis) and controls will be analyzed by next-generation RNA sequencing. The effect of identified candidate genes on Treg function/phenotype will be validated using lentiviral knocked-down/-in experiments.3.To investigate the role of the gut microbiota on myeloid LSCs in mice and humans. The question whether microbes in the gut can affect LSCs in the BM will be analyzed in congenic CML and AML mouse models using gnotobiotic mouse strains. The human relevance will be assessed by 16S RNA sequencing of feces from newly diagnosed AML patients and correlating the results to LSC numbers and Treg phenotype and function. Together, these lines of research will help to understand the role of Tregs and the gut microbiota in myeloid leukemia and explore the possibility to target Tregs and the gut microbiota to eliminate LSCs.
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