Overcoming immune evasion in myelodysplastic syndrome by manipulating PD-1H
EvansMDS Young Investigator Award
The incidence of Myelodysplastic syndrome (MDS) has been increasing as life-expectancy is prolonged. Treatment options in MDS are limited, highlighting the need for novel approaches. Despite rapid advancement of immunotherapies in solid tumors, immunotherapies in myeloid leukemia including MDS have not been successful. Limited understanding of the mechanisms of immune evasion in MDS prevents the successful application of current immunotherapies in these diseases. The mechanisms of immune evasion in MDS may include the expression of co-inhibitory molecules, suppressor cells and poor immunogenicity; however, dissection of the mechanisms of resistance remains an unmet scientific need. Here, we propose to define the mechanisms of immune evasion of MDS and implement an approach to overcome it by manipulating Programmed Death-1 Homolog (PD- 1H, VISTA). PD-1H is a recently identified co-inhibitory molecule that induces immune evasion in solid tumors. We observed that the expression of PD-1H is high in primary human AML and MDS bone marrow cells and that PD-1H blockade inhibits murine myeloid leukemia cell growth in vivo in a syngeneic transplant model. Importantly, our preliminary results also show that DNMT inhibition (DNMTi) potentiates the anti-leukemic effect of PD-1H blockade. The mechanisms behind these biological effects are unclear, but could be exploited for therapeutic uses. In this application, we will test our central hypothesis that PD-1H induces immune evasion of MDS, and that DNMTi can potentiate the anti-MDS effect of PD-1H blockade by enhancing immunogenicity of MDS. The overall goals of this project are to (1) develop an immunotherapeutic approach in MDS using a novel co-inhibitory molecule blockade, (2) test our hypotheses using an immune constituted patient-derived xenograft (PDX) model of human MDS.