Targeting the MMP-13/PD-1H signaling axis for multiple myeloma bone disease and immunosuppression
Suzanne Lentzsch
MD PhDColumbia University Medical Center
Project Term: July 1, 2022 - June 30, 2025
Multiple myeloma is an incurable blood cancer complicated by bone diseases and compromised immune system. Our work indicated that checkpoint inhibitor PD-1H(VISTA) functions as the MMP-13 receptor, and the MMP-13/PD-1H signaling axis plays a critical role in multiple myeloma induced bone disease and immunosuppression. Therefore, immunotherapy targeting the novel MMP-13/PD-1H interaction module represents a novel approach to cure this devastating cancer.
Multiple myeloma is a plasma cancer which remains incurable. Immune system is largely compromised in multiple myeloma patients, resulting in the incapability of immune cells to eradicate myeloma cells and pathogens. In addition, over 80% of patients with multiple myeloma develop skeletal lesions, resulting in bone pain, pathologic fractures and spinal cord compression which rarely repair even after disease remission. Current agents including bisphosphonate therapy could only partially inhibit the bone lesions but also cause severe side effects including acute renal failure, albuminuria and osteonecrosis of the jaw. Novel treatment is urgently needed to increase the therapeutic outcome.
It is known that multiple myeloma cells produce a set of factors that activate the bone resorption cells called osteoclasts, hence cause the extensive bone lesions in patients. Our work identified that matrix metalloproteinase 13 (MMP-13) is a critical factor that is highly produced by multiple myeloma cells and increases the bone resorption activity of osteoclast. Silencing the expression of MMP-13 in multiple myeloma cells significantly decreased the bone lesions in a mouse multiple myeloma bone disease model, indicating MMP-13 is a potent therapeutic target to inhibit myeloma bone disease. Importantly, we also found that MMP-13 is a potential immune inhibitor by suppressing T cells activation and proliferation. Our mechanism study further identified the novel immune modulator programmed death 1 homologue PD-1H as the cell receptor of MMP-13, and mediates MMP-13’s function in activating osteoclasts and suppressing immune cells. Thereby, our work, for the first time, presents MMP-13/PD-1H axis as a novel critical module that potentially controls both bone disease and immune surveillance escape in multiple myeloma patients.
Based on our finding, targeting MMP-13/PD-1H interaction may represent a novel potent treatment to cure bone disease, boost immune system, and subsequently inhibit tumor growth in multiple myeloma. In this proposed study, we will validate the effects of MMP-13/PD-1H antibodies on multiple myeloma bone disease and immune suppression by a profound set of molecular and cellular biology experiments, various animal model studies, and high-throughput patient biopsy examinations. The success of this project will validate the feasibilities of targeting the novel MMP-13/PD-1H axis for this devastating disease.