Blocking the PCNA/NKp44 checkpoint to stimulate NK cell responses to multiple myeloma

Natural killer (NK) cells are normal white blood cells of the innate immune system that play an important role in attack of multiple myeloma (MM) tumor cells, especially in early stages of disease. Despite some improved overall survival using newly developed immunotherapeutic agents over the past decade, MM remains an essentially incurable disease, and new therapies are needed. Collaboratively, we identified a novel pathway by which the NKp44 receptor on human NK cells recognizes proliferating cell nuclear antigen (PCNA) expressed on the surface of tumor cells. The recognition of PCNA by NKp44 inhibits anti-tumor responses by NK cells. We recently developed an anti-PCNA antibody that blocks NKp44 recognition of PCNA to restore NK cell responses toward PCNA-expressing tumors. Experiments in this proposal will explore the role of the PCNA/NKp44 interaction in repressing NK cell responses toward MM and the effectiveness of our anti-PCNA antibody in restoring NK cell responses. We expect to accumulate preclinical evidence demonstrating that antibody-mediated blockade of the PCNA/NKp44 interaction can promote NK cell responses toward myeloma. Such evidence could potentially support a future clinical trial to test anti-PCNA antibody as a novel immunotherapeutic agent to treat MM patients.