Supervisors info:
Βεργίνης Παναγιώτης, Ερευνητής Γ, ΙΙΒΕΑΑ
Μπούμπας Δημήτριος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ρουμπελάκη Μαρία, Επ. Καθηγήτρια, Ιατρική Σχολή – ΕΚΠΑ
Summary:
Immune checkpoint inhibitors (ICI) has revolutionized cancer therapeutics, yet a sizable portion of patients is associated with low response rates or side effects (immune related Adverse Events, irAE). A major impediment in the effectiveness of ICI therapy is the generation of cells with immunosuppressive capacity that home to tumor microenvironment (TME). These cells are generated via an altered program of hematopoiesis. Even though most studies have focused on the role of ICI therapy in tumor cells and immune cells in the periphery, the effect of this therapy in the generation of these cells, has remained elusive. Hematopoiesis primarily occurs in the bone marrow, where hematopoietic stem and progenitor cells (HSPC) are responsible for the generation of all blood cell types. Although their function in tumor progression is acknowledged, their capacity to be targeted by ICI and reshape their differentiation potential is yet to be defined.
Herein, we demonstrate that C57BL/6 melanoma bearing mice that receive anti-PD-L1 therapy, have a marked increase in the frequency of their HSPC population in the bone marrow, during early stages of the disease. We determine that anti-PD-L1 immunotherapy targets those cells, shown as decrease in the mean fluorescent intensity (MFI) compared to the control, untreated mice, group. Also, this immunotherapy scheme is associated with shifts in the frequency of immune cell population, such as total Dendritic cells (DC), Immature myeloid cells (IMC), B cells and T cells, in the bone marrow. We also report a marked increase in the DC population in peripheral blood of anti-PD-L1 melanoma bearing mice, concurrent with a decrease in the frequency of MDSC. In the spleen DC and MDSC frequencies are decreased associated with an increase in the MHCII expression of the MDSC population.
To sum up our results indicate that anti-PD-L1 might act in a previously neglected manner, influencing the HSPC compartment in the bone marrow, pushing them to proliferate and alter their output. Investigation of the mechanisms responsible could improve ICI therapy efficacy and possibly limit the extent of irAE developed after treatment.
Keywords:
Bone marrow, Immunotherapy, Hematopoietic stem cells, HSC, Melanoma, Anti-PD-L1
