Mesenchymal Stem Cells in Myeloid Malignancies: A Focus on Immune Escaping and Therapeutic Implications

Abstract

The importance of the bone marrow microenvironment forming the so-called niche in physiologic hemopoiesis is largely known, and recent evidences support the presence of stromal alterations from the molecular to the cytoarchitectural level in hematologic malignancies. Various alterations in cell adhesion, metabolism, cytokine signaling, autophagy, and methylation patterns of tumor-derived mesenchymal stem cells have been demonstrated, contributing to the genesis of a leukemic permissive niche. This niche allows both the ineffective haematopoiesis typical of myelodysplastic syndromes and the differentiation arrest, proliferation advantage, and clone selection which is the hallmark of acute myeloid leukemia. Furthermore, the immune system, both adaptive and innate, encompassing mesenchymal-derived cells, has been shown to take part to the leukemic niche. Here, we critically review the state of art about mesenchymal stem cell role in myelodysplastic syndromes and acute myeloid leukemia, focusing on immune escaping mechanisms as a target for available and future anticancer therapies.

Prevention of relapse after allogeneic stem cell transplantation in acute myeloid leukemia: Updates and challenges

“…Complete haplotype loss is seen in patients who relapse following haploidentical transplants and can occur in up to one third of these patients . The microenvironment of the bone marrow niche may protect malignant cells from immune surveillance or death from cytotoxic agents . Furthermore, reduced intensity and NMA conditioning may not suppress aggressive disease enough to allow GVL to develop, especially in the setting of MRD .…”

Epidemiology and biology of relapse after stem cell transplantation

“…14 (ii) The number of minor histocompatibility antigens (mHA) as the primary targets of GVL effects 15 is continuously increasing (now over 50) 16. Some mHAs are preferentially expressed by the hematopoietic system, and T cells may target them as self- or allo-restricted peptide.…”

“…The bone marrow microenvironment seems to be ideal for this approach since it constitutively expresses MHC Class II on stromal cells. 26 Considering the crucial role of the microenvironment for leukemic cell survival and escape 14 , it is obvious that targeting cancer stroma could be used to eradicate residual cancer cells. Destroying the stromal bone marrow microenvironment in which the leukemia cells reside would be restricted to the immediate vicinity of the cancer cells.…”

Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders

“…This results in a diminished cell cycle activity of HSPCs cultured on MDS-MSCs, highlighting that impaired stromal support contributes to ineffective hematopoiesis [98,112,113]. Moreover, several studies demonstrated an altered immunomodulatory function of MDS-MSCs, affecting tumor immune surveillance [114]. Evidence to date suggests that MSCs from neoplastic niche are educated to polarize macrophage toward an M2, anti-inflammatory, phenotype and they are responsible for increase Treg through the secretion of indoleamine 2,3-dioxygenase (IDO).…”