Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Abstract

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

Multiparametric Flow Cytometry for MRD Monitoring in Hematologic Malignancies: Clinical Applications and New Challenges

“…To date, CD123 and CD133 represent the most promising markers for LSC tracking (with a backbone including CD34, CD38, CD117, CD33, CD90, and CD45), and are also emerging as attractive targets for novel immunotherapies [ 11 ]. In particular, CD123 antigen (i.e., IL-3 receptor alpha chain) has attracted considerable attention: recently validated as main diagnostic marker for blastic plasmacytoid dendritic cell neoplasm (BPDCN), its expression has been reported in several cancers, including AML, myelodysplastic syndromes (MDS), myeloproliferative neoplasms, systemic mastocytosis, acute lymphoblastic leukemia (ALL), Hodgkin lymphoma, and hairy cell leukemia (HCL) [ 12 , 13 ]. In AML, CD123 was found to be significantly expressed by LSCs as well as by more differentiated leukemic blasts (but absent in the normal counterpart), and to correlate with the presence of FLT3/ITD-positive clones, thus representing a negative prognostic factor at diagnosis [ 14 , 15 , 16 ].…”

Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies

“…This group of disorders is encompassed by polycythemia vera (PV), which typically display a high number of red cells, usually in conjunction with thrombocytosis and essential thrombocythemia (ET), characterized by megakaryocyte expansion and increased platelet count. The main features of primary myelofibrosis (PMF) are peripheral leuko-erythroblastosis, massive splenomegaly, and BM fibrosis [202][203][204]. ET or PV may potentially evolve into either end-stage myelofibrosis with BM failure or the development of secondary acute leukemia [205].…”

Primary Immune Thrombocytopenia and Essential Thrombocythemia: So Different and yet Somehow Similar—Cases Series and a Review of the Literature

“…Dysfunction of T cells is related, among others, to programmed cell death protein-1 (PD-1) overexpression [48,49]. The overexpression of PD-1 ligand 1, in JAK2V617F-positive cells (monocytes, myeloid-derived suppressor cells, megakaryocytes and platelets), is induced by the overactivation of JAK/STAT pathways [12,50,51]. Moreover, JAKV617F-positive cells are able to produce a large amount of reactive oxygen species (ROS), which affect T cells negatively [50,52].…”

“…The overexpression of PD-1 ligand 1, in JAK2V617F-positive cells (monocytes, myeloid-derived suppressor cells, megakaryocytes and platelets), is induced by the overactivation of JAK/STAT pathways [12,50,51]. Moreover, JAKV617F-positive cells are able to produce a large amount of reactive oxygen species (ROS), which affect T cells negatively [50,52]. Currently, JAK2 inhibitors are used in some autoimmune disease therapies (for example rheumatoid arthritis, psoriasis) [53].…”