Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities

Abstract

Myeloid malignancies are clonal disorders of the progenitor cells or hematopoietic stem cells, including acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic cells affect the proliferation and differentiation of other hematopoietic lineages in the bone marrow and peripheral blood, leading to severe and life-threatening complications. Mesenchymal stromal cells (MSCs) residing in the bone marrow exert immunosuppressive functions by suppressing innate and adaptive immune systems, thus creating a supportive and tolerant microenvironment for myeloid malignancy progression. This review summarizes the significant features of MSCs in myeloid malignancies, including their role in regulating cell growth, cell death, and antineoplastic resistance, in addition to their immunosuppressive contributions. Understanding the implications of MSCs in myeloid malignancies could pave the path for potential use in immunotherapy.

Keywords: Cell differentiation; Mesenchymal stromal cells; Myeloid cells; Myeloid malignancies; T-cell immunosuppression therapy.

Fig. 1

Main features of Acute Myeloid Leukemia and Mesenchymal Stroma Cells: The most common mutation in AML is a mutation in the Flt3 gene, which is also a marker of poor prognosis, and provokes intracellular MAPK, STAT, and AKT signals. Meanwhile, MSCs can induce or reduce malignant cell proliferation and promote chemoresistance along with promoting immunosuppression protecting neoplastic cells from immunosurveillance. For more details, see the text. Purple indicates the main molecular characteristic of AML, and red indicates the main aspects of MSCs in interaction with the neoplastic cells. MSC, mesenchymal stroma cells; AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3; TGF-β, Transforming growth factor-beta; ALDH2, aldehyde dehydrogenase-2; IFNγ, interferon-gamma; VCAM-1, vascular cell adhesion molecule-1; VLA-4, very late antigen-4; ICN, intracellular domain of Notch; MAPK, mitogen-activated protein kinases. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Main features of Myelodysplastic Syndrome and Mesenchymal Stroma Cells: the most common aspect of MDS classification is the presence of ring sideroblasts and chromosomal abnormalities, such as del5q, accompanied by NRAS and RUNX1 mutations, among others. In turn, MSC promotes MDS cell proliferation and viability and produces CXCL12 chemokine related to the survival/anti-apoptotic effects on MDS cells. Also, MSC exhibits increased adipogenesis differentiation as well as increased senescence frequency. Moreover, MSCs secreted prostaglandins that collaborated with their immunosuppression activities. Purple indicates the main molecular characteristic of AML, and red indicates the main aspects of MSCs in interaction with the neoplastic cells. MDS, myelodysplastic syndrome, MSC, mesenchymal stroma cells; COX2, cyclooxygenase-2; CXCL12, C-X-C motif chemokine ligand 12, RUNX-1, runt-related transcription factor 1. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Main features of Chronic Myeloid Leukemia and Mesenchymal stroma cells. CML is a type of MPN identified by t(9; 22) BCR-ABL1 reciprocal chromosomal translocation. The tyrosine kinase coded for by the abnormal BCR-ABL1 fusion gene provokes hyperactivation of intracellular MAPK and PI3K/AKT signaling and is often accompanied by TP53, MYC, and KRAS gene mutations. MSC may inhibit CML cell proliferation, likely to IFNγ secretion, while protecting cells from cell death and promoting chemoresistance via the IL-7/JAK1/STAT5 axis. Purple indicates the main molecular characteristic of AML, and red indicates the main aspects of MSCs in interaction with the neoplastic cells. CML, chronic myeloid leukemia; MSC. Mesenchymal stroma cells; IFNγ, interferon-gamma; IL-7, interleukin-7; MAPK, mitogen-activated protein kinases. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Main features of Philadelphia (Ph)-negative Myeloproliferative neoplasms and mesenchymal stroma cells. Philadelphia (Ph)-negative Myeloproliferative neoplasms (Ph-MPN) group of disorders mainly encompasses Polycythemia vera (PV), Essential thrombocythemia (ET), and Primary myelofibrosis (PMF) characterized by mutations in JAK2, CALR, and MPL as shown in the inserted table. In MPN cells, the hyperactivation of JAK2 provokes constitutively activation of NF-ĸB, STAT1, STAT3, and HIF-1α signaling. In turn, MSC promotes MPN cell proliferation and therapy resistance. Moreover, MSC contributes to myelofibrosis due to a profibrotic cytokine milieu, alarmin complex S100A8/S100A9, and leptin receptors also contribute to a bone marrow fibrotic stage Additionally, MSC displays an imbalanced tendency towards osteogenesis differentiation. Purple indicates the main molecular characteristic of AML, and red indicates the main aspects of MSCs in interaction with the neoplastic cells. RUNX-2, runt-related transcription factor-2; OSP, osteopontin; HIF-1α, hypoxia-inducible factor-1; STAT, signal transducer and activator of transcription; NF-ĸB, nuclear factor kappa B; MAPK, mitogen-activated protein kinases. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 5

An overview of the immunosuppressive mechanisms of MSCs: MSCs have a potent immune-suppressive function on T-cells and may express and release proteins and molecules that inhibit their activation and function. MSC, mesenchymal stroma cells; iNOS, inducible nitric oxide synthase; NO, nitric oxide; COX2, cyclooxygenase-2; PGE2, prostaglandin-2; IDO, indoleamine 2,3-dioxygenase; Trp, tryptophane; CD39, triphosphate diphosphohydrolase-1 and CD73, ecto-5′-nucleotidase; PD-L1, PD-L2, programmed death-ligand 1, -ligand 2.

Fig. 6

Mesenchymal stroma cells and myeloid malignancy therapies: MSCs are being targeted for developing new therapeutic strategies to enhance current treatments due to their involvement in myeloid neoplasm pathogenesis. The figure summarizes the main aspects of MSC implications in myeloid malignancy therapy discussed in the main text, such as influencing tumor microenvironment (TME) by IL-7 and IL-12 secretion, TGF-β inhibition, chimeric antigen receptor T (CART) and immune checkpoint inhibitors (ICI). MSC, mesenchymal stroma cells; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; CML, chronic myeloid leukemia; MPN, Philadelphia chromosome-negative myeloproliferative neoplasms.