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 increase in 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 them containing more 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 markers 4.
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 immunity 5. In tumors and inflammatory disorders T cells represent the main target of MDSC-induced immune tolerance 1,6. 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 with a decline of functional capacity of both the adaptive and innate immune systems, in a process defined as immunoscenescence. Although the adaptive immune response has been more extensively investigated, some works document the significant impact of ageing on the innate compartment as well 6,8,9. In fact, neutrophils, dendritic cells and monocytes in aged individuals show a reduced functional activity 10-13. In addition, during aging an increase of regulatory T cells, a loss of T helper CD4+ and cytotoxic CD8+ T cells and an alteration of their functional capacities is observed, probably due to lower production of lymphoid cells by the bone marrow and to thymic involution, which reduces the release of naïve T cells. This is accompanied by a number of events including a reduced proliferative ability upon stimuli, as well as telomeres erosion, accumulation of memory T cells from chronic infections and replicative senescence upon persistent antigen exposure 14-16. In the same context MDSCs accumulate and exacerbate the process by impairing T cell proliferation and function, and producing large amounts of pro-inflammatory cytokines 5.
Aging is also associated with a chronic, low-grade inflammation state called inflammaging 17. 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 18. In particular, one of the hallmarks of the alterations in the BM during aging is the increased myelopoiesis, associated with a concomitant decrease in lymphopoiesis.
Our group demonstrated that GM-CSF, G-CSF, and IL-6 allow the in vitro generation 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 patients 19. BM-MDSCs are a heterogeneous collection of immature myeloid cells, but only the most immature subset from BM-MDSCs, with morphology and phenotype of promyelocytes (immature-BM-MDSC, i-BM-MDSC) is entirely responsible for the suppression mediated by BM-MDSCs 19.
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 20,21, while only a few works have documented it also in humans 22-24.
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 compare the 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.