Thesis title: Myeloid Derived-Suppressor Cells as A Potential Target of Immunotherapy in Notch Dependent T-Cell Acute Lymphoblastic Leukemia
Notch receptors play crucial roles in T-cell development, and their dysregulation leads to the development of T-cell Acute Lymphoblastic Leukemia (T-ALL), a condition that, as of now, lacks a definitive cure. Notch3 transgenic mice (N3-tg) represent a well- established model for T-ALL, where the constitutive activation of the receptor in immature thymocytes initiates an aggressive disease characterized by the expansion of tumoral T cells in the periphery. These tumor cells can trigger a Notch/IL-6-dependent accumulation of Myeloid-Derived Suppressor Cells (MDSCs), which, in turn, support tumor progression. MDSCs are an immature cell subset that inhibits immune responses, creating a conductive environment for tumor growth. Programmed cell death 1 (PD-1) is an inhibitory receptor of immune responses, recognized for its role as a suppressor of T-cell activation and proliferation when interacting with the PD-L1 ligand. MDSCs contribute to tumor progression through various mechanisms, including the expression of PD-L1, resulting in the inhibition of PD-1 expressing cells within the tumor microenvironment, such as T- and NK-cells.
The main aim of my thesis was to identify MDSC targets and mechanisms of action in the tumor microenvironment of our Notch-dependent murine model of T-ALL, with regard to their potential role in inhibiting NK activity, possibly through the PD-1/PD-L1 axis. Thus, this research ultimately aims to develop an innovative combined therapy for T-ALL, targeting tumor T cells, enhancing NK activity, and modulating MDSC function.
My data demonstrated that in N3-tg mice, number and function of NK cells decline significantly, while the percentage of them expressing PD-1 increases, during disease progression. This coincided with an expansion of functional MDSCs and in particular of the PD-L1+ fraction. This inverse correlation suggests us that NK impairment could be driven by MDSCs. Indeed, through in vitro cytotoxicity assay based on co-culture of NK cells with MDSCs, both from spleen of N3-tg mice, we confirmed that MDSCs can significantly hinder NK cell function.
Finally, treating N3-tg mice with anti-PD-L1 blocking antibodies markedly inhibits T- ALL progression, by significantly reductions in splenomegaly and absolute count of tumor cells. Moreover, the treatment led to a substantial decrease in overall MDSC numbers, particularly within the PD-L1-expressing subset. Concurrently, there was a noticeable expansion of PD-1+ NK cells, exhibiting a significantly heightened cytotoxic activity compared to the control group.
In conclusion, my results suggest that in Notch-dependent T-ALL, MDSCs may hinder the anti-tumor activity of NK cells via the PD-1/PD-L1 axis, thus favoring disease progression. Then, molecules and cells of this network could potentially serve as prognostic markers and/or targets for innovative therapies.