Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients

Abstract

Human granulocytic myeloid-derived suppressor cells (G-MDSCs) have been described as low-density immunosuppressive CD66b+CD33dimHLA-DR-granulocytes that co-purify with mononuclear cells after density gradient centrifugation of blood from cancer patients. The role of G-MDSCs in Hodgkin (HL) and non-Hodgkin lymphoma (NHL) remains unclear.The percentage and immunophenotype of CD66b+CD33dimHLA-DR-cells were analyzed in PBMCs from HL and B-cell NHL patients (n = 124) and healthy donors (n = 48). The immunosuppressive functions of these cells were tested in vitro. Correlations between CD66b+CD33dimHLA-DR-cells and patient clinicopathological features and outcome, were evaluated.CD66b+CD33dimHLA-DR-cells were increased in PBMCs from HL and B-cell NHL patients as compared to healthy donors: 2.18 (0.02–70.92) vs 0.42 (0.04–2.97), p < 0.0001. Their percentage remained significantly higher even considering HL (n = 31), indolent (n = 31) and aggressive (n = 62) B-cell NHL patients separately: 1.54 (0.28–26.34), 2.15 (0.02–20.08), and 2.96 (0.25–70.92), respectively, p < 0.0001. CD66b+CD33dimHLA-DR-cells in patient PBMCs were mostly composed of mature CD11b+CD16+ low-density neutrophils in an activated status, as revealed by their higher CD11b and CD66b expression as compared to conventionally isolated (normal-density) autologous or healthy donor neutrophils. The in vitro depletion of CD66b+ cells from patient PBMCs restored the proliferation of autologous T cells. Higher frequencies of CD66b+CD33dimHLA-DR− G-MDSCs correlated significantly with unfavorable prognostic index scores and a shorter freedom from disease progression.PBMCs from HL and B-cell NHL patients contain a population of CD66b+CD33dimHLA-DR− G-MDSCs, mostly composed of activated low-density neutrophils with immunosuppressive properties. These findings disclose a previously unknown G-MDSC-mediated mechanism of immune-escape in lymphomas, therefore anticipating possible targets for therapeutic interventions.

Human neutrophils in the saga of cellular heterogeneity: insights and open questions

“…acquisition of a higher forward scatter and a lower side scatter by flow cytometry) ( Table 1). In our studies, immunosuppressive LDNs/G-MDSCs present in either lymphoma patients (46), or G-CSF-treated healthy donors (O. Marini, C. Tecchio, M.A. Cassatella and P. Scapini,unpublished observations), were mostly constituted by activated mature neutrophils.…”

“…Whatever the case is, the phenotypic and functional features of the LDNs to date described in various diseases are discussed below and summarized in Tables and . It must be pointed out that, despite the several unanswered questions on their features, there is a considerable clinical interest around LDNs, as their frequency often correlates with disease severity and/or responsiveness to treatment in many pathologies, including cancer , sepsis , HIV‐1 , and mycobacterial infection and autoimmune disorders .…”

“…LDNs displaying immunosuppressive functionsmore commonly known as granulocytic myeloid-derived suppressor cells (G-MDSCs)have been originally identified within the PBMC fraction from patients with several types of solid tumors [ (36,(52)(53)(54)(55) and Table 1 for a list of updated studies]. More recently, evidence on the presence of immunosuppressive LDNs/G-MDSCs have also been reported in patients with hematological malignancies (45,46,(56)(57)(58)(59), as well as in a broad variety of acute and chronic inflammatory disease conditions, including HIV-1 infection (35,48,60), sepsis (61, 62), graft-versus-host disease (GvHD) (63), and trauma (64). Interestingly, immunosuppressive LDNs/ G-MDSCs have been described also in conditions in which an altered T cell tolerance is present, including in pregnancy (37,65), in neonates (37,66,67) or in healthy volunteers receiving G-CSF for stem cell mobilization (68,69).…”

MiR‐30a increases MDSC differentiation and immunosuppressive function by targeting SOCS3 in mice with B‐cell lymphoma

“…MDSC recruitment could promote the progression of B cell lymphoma by recruiting and activating regulatory T cells (Treg) via arginase . Moreover, the numbers of both G‐MDSCs and M‐MDSCs were also increased in B‐cell lymphoma patients and their immunosuppressive functions were enhanced via the release of IL‐10 . Of note, MDSCs are potent immunosuppressive cells from the microenvironment‐mediated conversion of myeloid cells.…”

Myeloid-Derived Suppressor Cells in Some Oncohematological Diseases

“…-достоверно коррелирует с неблагоприятным прогнозом и с неудовлетвори-тельными показателями выживаемости, свободной от прогрессирования заболевания [71]. Тем не менее остается неясным, являются ли миелоидными супрес-сорами клетки, не попавшие во фракцию МПК.…”