Notch receptors influence deeply T cell biology and their dysregulations are frequent causative events of 'T-cell Acute Lymphoblastic Leukemia' (T-ALL), an aggressive cancer with no resolutive cure. Notch pathway regulates transformed cells, but also their interactions with microenvironment, where the recruitment of immune-suppressive cells supports immune escape and tumor growth. In this context, Myeloid-Derived Suppressor Cells (MDSCs) are able to suppress anti-tumor responses of both innate (NK cells) and adaptive (T cells) origin. The PD-1/PD-L1 axis is a prominent pathway in the regulation of immune-responses. PD-1 (Programmed cell death-1) is well-known as an inhibitor of T-cell activation, upon interaction with the PD-L1 ligand. This ligand is also widely expressed on tumor cells that inhibit the cytotoxic activity against the tumor of T- and NK-cells, that express PD-1. Targeting the PD-1/PD-L1 axis can restore anti-tumor immunity, thus improving chemotherapy effects and patient survival, as described in solid tumors (i.e. melanoma, lung cancer, renal cancer) and hematological malignancies (such as Hodgkin lymphoma, adult T-cell leukemia/lymphoma, Multiple Myeloma). Notably, PD-1/PD-L1 expression can be altered on TME components, such as NKs and MDSCs and may regulate their behavior towards cancer cells. To date, no relevant results have been produced about the possible influence of the PD-1/PD-L1 axis on interaction between leukemic cells and TME subsets in T-ALL.
Previous observations in transgenic murine model of Notch-dependent T-ALL (N3-tg mice), report induction of MDSCs, as well as impaired activity of NKs, that associate with dysregulated expression of PD-1/PD-L1 molecules on these subsets. Thus, we aim to dissect the crosstalk between T-ALL cells, NKs and MDSCs, possibly mediated by the PD-1/PD-L1 axis, in the final attempt to propose this network as target of innovative therapies and to individuate new prognostic factors for the disease.
