Inhibiting ligand-driven BMP Signaling to Overcome Immunotherapy Resistance  

The use of immunotherapies has revolutionized treatment for late-stage melanoma patients. These therapies have extended survival for many patients who would have previously succumbed to their disease. Unfortunately, resistance to immunotherapies is common, evident either at the outset of treatment or after some time when portions of the original tumor grow and expand in spite of treatment. Resistance is commonly characterized by poor immunogenicity of tumor cells, in that they fail to elicit a response by the T cells that are unleashed by immunotherapies. Addressing this resistance can be done by using supplementary therapies that target immunotherapy-resistant melanoma cells through immune-independent mechanisms or by using enhancement therapies that can augment immunotherapy responsiveness and block emergent resistance. My laboratory previously discovered a vulnerability of melanoma cells that is rooted in their use of bone morphogenetic protein (BMP) signaling. This is a cell-cell communication pathway that is turned on when one cell secretes a signaling ligand protein, which is then bound by receptors on receiving cells, leading to BMP pathway activation in the receiving cell. A normal function of BMP signaling is to prevent melanocyte differentiation during embryonic development. Melanomas reawaken this pathway by inappropriately expressing a BMP ligand called GDF6. GDF6 then activates BMP signaling in the tumor and keeps melanoma cells in an undifferentiated state that enables their continued, unrestrained cell division. When we disable GDF6-driven BMP signaling in melanoma cells it causes them to differentiate and then die.  

About 75% of human melanomas have active GDF6-driven BMP signaling, making it a therapeutic target that could impact a large fraction of melanoma patients. To target this pathway, we have created a monoclonal antibody that binds to and inhibits GDF6. This antibody kills melanoma cells in culture and blunts the growth of human melanoma tumors in mice. Thus far we have targeted melanoma cells and tumors that are naïve to immunotherapy. As part of this proposal our first aim will test whether inhibition of GDF6-driven BMP signaling can target immunotherapy-resistant cells and tumors without the involvement of the immune system. Additionally, we have discovered that treatment with anti-GDF6 antibody potentially makes melanoma cells more visible to the immune system. For this reason our second aim will test whether anti-GDF6 therapy could augment immunotherapies. Taken together, inhibition of GDF6-driven BMP signaling has the potential to be effective against a large fraction of melanomas through one mechanism that is independent of the immune system and another mechanism that cooperates with immunotherapies. Both mechanisms have the potential to blunt the resistance that is often seen with melanoma immunotherapy.