Siah2 Ubiquitin Ligase in Immune Checkpoint and Melanomagenesis

With the significant advance made in recent years in immune therapy, and more specifically in immune checkpoint-based therapy, we find ourselves often amazed, albeit gratified, by the success and advance in therapy of the most devastating cancers. There is an often-used analogy to the brakes on a car, that is, immune checkpoint therapy reduces brake efficiency, thereby increasing efficiency of the drive – as compared to a tumor attack. Only that, the brakes serve to prevent accidents, and so it is the immune system brakes that prevent the self-attack often associated with autoimmune disorders. With this analogy, several drugs that target different brake systems were developed and are now in a large number of clinical trials. Unfortunately, we do not always know which brake is better to inactivate, and we cannot anticipate which will result in an autoimmune disorder. Clearly the understanding of the different brake systems and their implications for different individuals (car types) requires much research and understanding. Thus, fundamental questions per the mechanism of actions of immune checkpoint therapy and hence selective success (i.e., in some but not other cases) remain elusive.

The proposed research has direct relevance to the Fiscal Year 2017 Peer Reviewed Cancer Research Program topic area of melanoma. The work outlined in this application is also responsive to the Military Relevance Focus Area as it addresses mechanistic aspects pertaining to diagnosis, monitoring, and treatment of melanoma that may affect the general population but have a particularly profound impact on the health and well-being of active duty Service members, Veterans, and their beneficiaries. This proposal is expected to fill important gaps in our understanding of mechanisms that govern tumor immunity, or the ability to manipulate the immune system to overcome cancer, in this case, melanoma. Using a genetic mouse model that lacks a single protein implicated in the control of protein stability, we found unanticipated yet effective inhibition of melanoma development. The inability of melanoma to grow in this genetic mouse model was linked to enhanced tumor immunity, and further, we were able to map specific components of the immune system that are enhanced in their activity and attack of the melanoma. These finding are most exciting since they provide us a clear path to understanding mechanisms underlying an immune system attack on melanoma. Our ability to dissect this observation will guide us in defining new players in the control of melanoma by the immune system. Our studies will identify components that can be targeted by novel therapies, or explain observations made in different systems but of which we lack understanding, thereby advancing our greater understanding of the immune system-interaction with and regulation of melanoma.

Returning to the car brakes analogy, our study will define whether we discovered a new brake system, or the make-up of a known one, which will allow us to better understand it, and better plan when to use it or not. Given the anticipated information, the proposed studies will gather information that can be further developed to inactivate a new brake or fine tune the inactivation of existing ones.

The relevance of these studies to military personnel and their family members is multifold. First, the incidence of melanoma continues to increase, not only in the general population but also in Army personnel, given the continued presence of our Soldiers and family members in high, sun-exposed areas. Second, the implications of our studies are likely to span beyond melanoma, since the regulation of the immune system, as identified in this particular case, is expected to be of relevance to other tumors that are subjected to immune control. Indeed, immune checkpoint therapy that was initially evaluated in melanoma is now assessed in a number of different tumor types. Third, the long-term impact of our study is likely to pave the road for new therapeutic modalities, which will be evaluated in melanoma but also other tumor types, of relevance to Army personnel and their family members.