Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immunosuppressive myeloid cells developing from myeloid progenitors, which are particularly enriched in pathological conditions such as cancer, infections, inflammation and sepsis 1-3. These pathological conditions determine an increasein circulating colony-stimulating factors (CSFs)as well as chemokines that stimulate the myelopoiesis and, consequently, the generation of immature MDSCs. Different subsets of human MDSCs have been documented in several types of tumors, and it appears that all MDSC phenotypes can be allocated to one of the three main subsets, each of themcontainingmore than one cell population. Monocytic MDSCs (M-MDSCs) share the morphology of monocytes and are characterized by the expression of CD14 and lack of CD15, polymorphonuclear MDSCs (PMN-MDSCs) are instead defined by the opposite expression of the myeloid markers (CD15+/CD14-), while more immature MDSCs (early-stage, e-MDSCs) lack the expression of both markers4.
These cells are released into the bloodstream and recruited to the affected tissues, where they proliferate and are activated by inflammatory factors, and suppress acute inflammatory reactions by inhibiting the functions of distinct components of innate and adaptive immunity5.In tumors and inflammatory disordersT cells represent the main target of MDSC-induced immune tolerance1,6.Indeed, MDSCs are involved in tumor angiogenesis, drug resistance and tumor progression and could represent a potential therapeutic target both in cancer and in chronic inflammatory diseases 3,7.
During aging several changes take place such as the dysregulation of the immune, central and peripheral nervous, endocrine and metabolic system. In particular, aging is associated witha decline of functional capacity of both the adaptive and innate immune systems, in a process defined as immunoscenescence;however these changes have a more significant impactonthe cells of the adaptive immunity than those of innate immunity6.There is an age-related loss of CD4+ and CD8+ T cells and an alteration of their functional capacities. The reduction of these cells seems to be linked to the decrease of the expansion of T cell clones and also to the proliferation ability after maturation 6. Moreover, there is an increase of regulatory T cells and a reshaping in the number of T helper populations associated with aging 6.
Aging is also associated with a chronic, low-grade inflammation state called inflammaging8.It appears that in the microenvironment of the bone marrow (BM)inflammaging affects haematopoietic stem cells, with a possible rebound on the myelopoiesis and lymphopoiesis process 9. In particular, one of the hallmarks of the alterations in the BM during aging is the increased myelopoiesis, associatedwith a concomitantdecrease in lymphopoiesis.
Our group demonstrated that GM-CSF, G-CSF, and IL-6 allow thein vitrogeneration of MDSCs from precursors present in human bone marrow aspirates of healthy donors, and named such cells BM-derived MDSCs (BM-MDSCs).Of note, these cells share the phenotype and the suppressive function of MDSCs isolated from cancer patients10. BM-MDSCs are a heterogeneous collection of immature myeloid cells, but onlythe most immature subset from BM-MDSCs, with morphology and phenotype ofpromyelocytes (immature-BM-MDSC, i-BM-MDSC) is entirely responsible for the suppression mediated by BM-MDSCs10.
Most of the works that advance that MDSC levels increase during aging have been obtained in mouse models in which these suppressive populations have been evaluated in the BM, spleen and circulation 11,12, while only a few works have documented it also in humans13,14. It is not clear if the increase of myelopoiesis, which occurs in aging, is associated with an increase of MDSCs generation in the BM of humans, and consequently with an increase of these cells in the blood circulation. In addition, there are no data showing whether aging impacts on the immunosuppressive ability of MDSCs.
Aim of this study is to comparethe induction of MDSCs from the BM of young and old individuals by using an optimized method to generate in four days MDSCs from precursor cells through cytokines treatment. Such cells are equivalent to MDSCs present in the blood of cancer patients and gives us the possibility to evaluate not only the expansion ability of the precursors, but also the immunosuppressive ability of the induced myeloid suppressor cells.