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.
In the last three decades an enormous advancement in understanding the molecular and cellular mechanisms involved in the development of 'T-cell acute lymphoblastic leukemia' (T-ALL), has been realized. In particular, many studies have defined a crucial role of Notch signaling dys-regulation in over the 50% of patients, thanks to the characterization of pre-clinical murine models. However, though standard chemotherapies have rendered curable this neoplasia, overall survival of T-ALL patients remains low, with about the 25-30% of pediatric and up to 60% of adult cases, that relapse and eventually die. One of the major reason for this clinical severity of T-ALL resides into the fact that different pathways are involved in the onset and progression of the disease. Notch signaling itself may interact, indeed, with many targets and regulators, and this intricate molecular network allows ultimately malignant cells to escape the standard strategies for the cure.
More recently, for many solid tumors and some hematological malignancies, the crucial role of Tumor Microenvironment (TME) components in influencing the survival and spreading of cancer cells has been reported. In particular, immune-suppressive cells, such as Myeloid-Derived Suppressor Cells, can be reprogrammed by cancer cells to inhibit anti-tumor responses, thus favoring tumor growth. Thus, the inhibition of MDSC activity, often in combination with immune-checkpoint control, is emerging as one of the most promising strategy to defeat cancer.
However, very few data has been generated in this context for T-ALL, to date. Not surprisingly, there are no next-generation therapies available in T-ALL, suggesting the urgent need for relevant pre-clinical models to identify and validate new targets and innovative treatment approaches.
We believe that our ambitious research proposal contains important innovative traits that derive from a strict adherence to the mission of the cluster1/Health of the new Horizon Europe program, which states 'The aims of this cluster include improving and protecting the health and well-being of citizens of all ages by generating new knowledge, developing innovative solutions...to prevent, diagnose, monitor, treat and cure diseases'.
Our major aim, indeed, is to explore the potential impact on the disease progression of the crosstalk between leukemic cells, MDSCs and NK cells in the TME of T-ALL, possibly mediated by the PD-1/PD-L1 axis. Notably, except for the leukemic cells, the role in T-ALL is undefined and probably under-estimated for all the actors included in this project.
We generated previous data on the accumulation of functional MDSCs in our pre-clinical model of Notch-dependent T-ALL (N3-tg mice). Further, we have preliminary results indicating an altered cytotoxic function and an enhanced expression of the PD-1 receptor in NK cells from these transgenic mice.
Overall, we believe that all the observations above represent a robust premise to explore the possibility that the TME could become for T-ALL an innovative target of therapy, based on the combined inhibition of immune-checkpoint signals, Notch pathway activation and MDSC suppressive function. As a secondary, but equally crucial achievement, we aim to unveil new prognostic factors for the disease.
Important guarantees for the achievement of the proposed objectives reside in the long-standing experience maturated by all the structured team members on the specific topic of the oncogenic role of Notch signaling, primarily in T-ALL, but also in other cancers. Besides, our Department infrastructures (that include Animal facility, advanced FACS- and 'FACS-assisted cell sorting'-equipments and fully equipped laboratories of molecular/cellular biology), allow the complete implementation of the proposed experiments.