Molecular and phenotypical mechanisms driving immune evasion in myeloid malignancies

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)