Molecular and phenotypical mechanisms driving immune evasion in myeloid malignancies

• Grant number: 21/06841-3
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: February 01, 2022
• End date: January 31, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Lorena Lôbo de Figueiredo Pontes
• Grantee: Lorena Lôbo de Figueiredo Pontes
• 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 researchers: Fabíola Traina ; Leandro Machado Colli ; Merixtell Alberich Jorda ; Robert Samuel Welner
• Associated research grant: 15/21866-1 - Cytokine-mediated regulation of normal and neoplastic hematopoietic stem cells by natural killer cells, AP.JP
• Associated research grant(s): 24/02164-5 - Leukemic susceptibility mediated by functional ligands of natural killer cells, AP.R; 24/00286-6 - Molecular and phenotypical mechanisms driving immune evasion in myeloid neoplasms, AP.R SPRINT
• Associated scholarship(s): 23/17838-9 - Phenotypic and Functional Characterization of NK and T Cells in a Murine Model of Acute Myeloid Leukemia, BP.MS; 23/17821-9 - Phenotypic Evaluation of Natural Killer Cells and T Lymphocytes During the Response and After Discontinuation of Tyrosine Kinase Inhibitor Treatment in Patients with Chronic Myeloid Leukemia, BP.DD; 23/12667-1 - Immunophenotypic characterization of NK cells in a Flt3-Tet2 murine model of Acute Myeloid Leukemia, BP.IC; + associated scholarships 23/01821-0 - Characterization of subpopulations of cytotoxic cells in murine models of myeloid leukemia, BP.DR; 23/02139-8 - To identify mechanisms and targets of the leukemic microenvironment's effect on dysfunctional immune cells, BP.DD; 22/09394-0 - Identification of immune evasion mechanisms in myeloid leukemias by mapping natural killer cells by single-cell transcriptomics, BP.PD - associated scholarships

Abstract

Natural Killer (NK) cells, the major subset among Innate Lymphoid Cells (ILCs), can affect frequency and self-renewal of normal hematopoietic stem cells (Figueiredo-Pontes et al, Stem Cell Reports, 2021). On the other hand, NK maturation dysfunction may contribute to leukemogenesis in myeloproliferative neoplasms (Bianco & Arantes et al, submitted Frontiers in Oncology, 2021) and Acute Myeloid Leukemia (AML). Our preliminary data suggest a shift of NK cells from highly cytotoxic toward immature cytokine-producing that favor survival of Leukemia Initiating Cells (LICs). Evidence of immune evasion in diverse models of neoplasia leads us to hypothesize that LICs are resistant to ILCs (specially NK cells). Therefore, in myeloid neoplasms, exposure to the leukemic cytokine milieu may prevent NK functional maturation and anti-leukemic activity. The following research plan will focus on the molecular variation of the immune cytotoxic cells and their immune evasion mechanisms on the pathophysiology of myeloid neoplasms. We intend to develop a transcriptional and immunophenotypical mapping of ILCs present in myeloid malignancies through single-cell RNA sequencing and multiparametric flow cytometry in MPN and AML cells. Chimeric leukemic models (Bcr-abl1, Jak2V617F and AML1-Eto9a) will be used to investigate mechanisms and pathways involved in the NK:LIC interaction. We expect that a robust characterization of Innate Lymphoid Cells (ILCs) by single-cell and functional assays will contribute for developing new strategies to reestablish the immune antitumoral capacity in myeloid malignancies, yet unfortunately rarely curable. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

COSTA, AMANDA FERNANDES DE OLIVEIRA; MARANI, LETICIA OLOPS; BIANCO, THIAGO MANTELLO; ARANTES, ADRIANA QUEIROZ; LOPES, IZABELA APARECIDA; PEREIRA-MARTINS, DIEGO ANTONIO; PALMA, LEONARDO CARVALHO; SCHEUCHER, PRISCILA SANTOS; SCHIAVINATO, JOSIANE LILIAN DOS SANTOS; BINELLI, LARISSA SARRI; et al. Altered distribution and function of NK-cell subsets lead to impaired tumor surveillance in JAK2V617F myeloproliferative neoplasms. FRONTIERS IN IMMUNOLOGY, v. 13, p. 15-pg., 2022-09-23. (21/06841-3, 15/21866-1)