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To identify mechanisms and targets of the leukemic microenvironment's effect on dysfunctional immune cells

Grant number: 23/02139-8
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2023
Effective date (End): January 31, 2027
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Lorena Lôbo de Figueiredo Pontes
Grantee:Rita de Cássia Barbosa Macedo
Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil
Associated research grant:21/06841-3 - Molecular and phenotypical mechanisms driving immune evasion in myeloid malignancies, AP.JP2

Abstract

To answer why cytotoxic subpopulations are dysfunctional in myeloid neoplasms, we need to investigate if the leukemic environment prevents ILCs maturation resulting in diminished antileukemic activity. This speculation is supported by preliminary data generated by Robert Welner's group. They have performed gene set analysis on a public dataset (GSE109125) to compare IL-6/STAT3 signature between different NK maturation stages in human samples. Interestingly, IL6/STAT3 transcription signature was found to be enriched in immature cytokine-producing NK subset in both species, suggesting that activation of this axis in leukemia may drive the functional skew. Next, single-cell RNA-seq data set (GSE116256) in bone marrow from AML patients and healthy volunteers was analyzed and showed downregulation of genes associated with NK cell maturation and cytotoxicity. The current proposal will explore the potential role of cytokines (such as IL-1², IL-6, IL-10, TNF±) on the activation of pathways like STAT3/STAT5, NF-kB, p38 MAPK, MEKK1, that can modify immune function by using leukemic mouse models. The following question is whether it is possible to counteract the microenvironment's detrimental effect on ILCs. Finally, if we are able to identify differential pathways or mediators of NK dysfunction in the myeloid models here tested, a future possibility can be to assess leukemia-associated changes in chromatin accessibility by ATAC-sequencing, specifically at the sites of the chosen molecules. We expect to characterize, in human samples of CML, MPN and AML the transcriptional and immunophenotypical patterns of NK and T cells. It will be possible to correlate these profiles in chronic and acute myeloid leukemias with the genomic tumoral landscape, signaling pathways and clinical outcomes associated with immune evasion as well as to elucidate potential mechanisms for ILC:LIC interplay. By the end of the project, we predict to generate data to understand the genetic variability that drives immune phenotypes of leukemic human samples and identify specific targets towards ILCs regulation as a tool to develop future immunotherapies in myeloid malignancies, also find specific profiles for ILCs function in the various genetic subtypes of myeloid neoplasms, making possible discover how the leukemic environment can modify immune cells as a tool to enhance their therapeutic function. (AU)

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