TY - JOUR
T1 - Myeloid-derived suppressor cell subtypes differentially influence T-cell function, T-helper subset differentiation, and clinical course in CLL
AU - Ferrer, Gerardo
AU - Jung, Byeongho
AU - Chiu, Pui Yan
AU - Aslam, Rukhsana
AU - Palacios, Florencia
AU - Mazzarello, Andrea Nicola
AU - Vergani, Stefano
AU - Bagnara, Davide
AU - Chen, Shih Shih
AU - Yancopoulos, Sophia
AU - Xochelli, Aliki
AU - Yan, Xiao Jie
AU - Burger, Jan A.
AU - Barrientos, Jacqueline C.
AU - Kolitz, Jonathan E.
AU - Allen, Steven L.
AU - Stamatopoulos, Kostas
AU - Rai, Kanti R.
AU - Sherry, Barbara
AU - Chiorazzi, Nicholas
N1 - Funding Information:
Acknowledgements This work was supported in part by a grant from the CLL Global Research Foundation to NC and by philanthropic contributions to NC and KRR from the Karches Family, The Nash Family Foundation, The Marks Foundation, and the Jean Walton Fund for Leukemia, Lymphoma, and Myeloma Research, and by contributions from the Paul Foundation to BS.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
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U2 - 10.1038/s41375-021-01249-7
DO - 10.1038/s41375-021-01249-7
M3 - Article
C2 - 33935280
AN - SCOPUS:85105165064
SN - 0887-6924
VL - 35
SP - 3163
EP - 3175
JO - Leukemia
JF - Leukemia
IS - 11
ER -