Myeloid-derived suppressor cell subtypes differentially influence T-cell function, T-helper subset differentiation, and clinical course in CLL

Gerardo Ferrer,Barbara Sherry,Andrea Nicola Mazzarello,Rukhsana Aslam,Aliki Xochelli,Jacqueline C Barrientos,Pui Yan Chiu,Florencia Palacios,Jonathan E Kolitz,R Kanti ,Stefano Vergani,Xiao‐Jie Yan ,Shih‐Shih Chen ,Sophia Yancopoulos,Kostas Stamatopoulos,Steven L Allen,Jan A Burger,Davide Bagnara,Byeongho Jung,Nicholas Chiorazzi

doi:10.1038/s41375-021-01249-7

Abstract

Cancer pathogenesis involves the interplay of tumor- and microenvironment-derived stimuli. Here we focused on the influence of an immunomodulatory cell type, myeloid-derived suppressor cells (MDSCs), and their lineage-related subtypes on autologous T lymphocytes. Although MDSCs as a group correlated with an immunosuppressive Th repertoire and worse clinical course, MDSC subtypes (polymorphonuclear, PMN-MDSC, and monocytic, M-MDSCs) were often functionally discordant. In vivo, PMN-MDSCs existed in higher numbers, correlated with different Th-subsets, and more strongly associated with poor clinical course than M-MDSCs. In vitro, PMN-MDSCs were more efficient at blocking T-cell growth and promoted Th17 differentiation. Conversely, in vitro M-MDSCs varied in their ability to suppress T-cell proliferation, due to the action of TNFα, and promoted a more immunostimulatory Th compartment. Ibrutinib therapy impacted MDSCs differentially as well, since after initiating therapy, PMN-MDSC numbers progressively declined, whereas M-MDSC numbers were unaffected, leading to a set of less immunosuppressive Th cells. Consistent with this, clinical improvement based on decreasing CLL-cell numbers correlated with the decrease in PMN-MDSCs. Collectively, the data support a balance between PMN-MDSC and M-MDSC numbers and function influencing CLL disease course.

Highlights

In chronic lymphocytic leukemia (CLL), a CD5+ B-cell progressively expands and accumulates in the bone
Using an HLA-DRloCD11b+CD33+ phenotype to define myeloid-derived suppressor cells (MDSCs) (Fig. S1) and expression of CD15 and CD14 to divide these into PMN-MDSCs and M-MDSCs subtypes (Fig. 1A and [24]), we found that the absolute numbers of MDSCs were significantly higher in 55 untreated CLL patients than 12 age-matched healthy individuals served as controls (HCs) (Fig. 1B)
We have quantified the absolute numbers of MDSCs and their lineage-based subtypes in the blood of CLL patients, their effects on the growth and maturation of naive T-lymphocytes to Th subsets, and their association with patient outcome

Summary

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In chronic lymphocytic leukemia (CLL), a CD5+ B-cell progressively expands and accumulates in the bone. Thessaloniki, Greece marrow and secondary lymphoid organs [1,2,3,4] At these sites, CLL cells engage in complex, incompletely defined interactions with other cell types such as non-leukemic T cells, myeloid cells, and mesenchymal stromal cells that are critical for survival and proliferation of the leukemia [5, 6]. T cells are a main target of myeloid-derived suppressor cells (MDSCs), the latter a heterogeneous population divisible into monocyte-like (CD14+, “M-MDSC”) and polymorphonuclear-like (CD15+, “PMN-MDSC”) subsets [12]. Both types can block T-cell growth [12] and modulate T-cell differentiation into functional T-helper (Th)-cell subsets [13]. Ibrutinib reduced significantly the numbers of MDSCs and PMN-MDSCs and altered MDSC-induced differentiation of autologous naive T (TN) cells toward Th1 and away from Th2 cells, thereby leading to a more protective, anti-leukemia TME

Materials and methods

Results

Discussion

Compliance with ethical standards