Tae Kon Kim, M.D., Ph.D.
2018 Funding recipient
Overcoming immune evasion in myelodysplastic syndrome by manipulating PD-1H
EvansMDS Young Investigator Award
Myelodysplastic syndrome (MDS) is a bone marrow cancer characterized by ineffective blood cell generation and leukemic transformation in bone marrow. Despite extensive research, a DNA methyltransferase inhibitor, azacitidine is the only treatment proven to prolong survival in higher risk (HR)-MDS besides allogeneic stem cell transplantation. Failure of DNA methyltransferase inhibitor therapy is common in MDS patients and has a dismal prognosis. No second-line treatment has improved survival in this setting, highlighting the need for novel approaches. Recently, a novel immunological approach to enhance anti-tumor immunity (immune checkpoint inhibitor) has been developed and successfully applied to stage IV melanoma, lung cancer, and bladder cancer. It was designed to induce sustained and augmented T cell activation against tumors by blocking pathways (i.e. PD1–PD-L1) that suppress T cell activation. These treatments function by manipulating the patient’s immune system into killing cancer cells. Unfortunately, MDS is resistant to this approach, likely due to the unique immune escape mechanisms including pathways other than PD1–PD-L1. PD-1H, a molecule homologous to PD-1, is an inhibitory molecule we recently identified. PD-1H is predominantly expressed in blood cells. Interestingly, we found that PD-1H is highly expressed in human MDS bone marrow. The mechanisms of PD-1H in inducing a poor immune response in MDS have not fully been elucidated. We will test our hypothesis that PD-1H induces a poor immunological response in MDS by carrying out mechanistic studies in humanized mice expressing human cytokines to promote human immune cell engraftment. Our long-term goal is to develop an effective immunotherapeutic approach for the management of MDS patients.