Unraveling Immunosuppressive Trafficking in Melanoma
Abstract
Within cancer cells, including melanoma, there is a command central from which most executive orders for growth, survival, and cell movement originate. Genetic mutations create the equivalent of commander-in-chief proteins within cancer cells. In about half of all melanoma originating in the skin, the initial order for growth emanates from an abnormal/mutated protein commander named BRAF. BRAF orders are executed by a hierarchy of subordinate proteins. Similar to successful military operations, cancer cells must have a reliable and efficient means of transporting commanders and their subordinates to strategic operative sites inside cells. ARF6 is a protein that coordinates such transportation within the cell. The role of ARF6 is similar to that of a train conductor, ensuring trafficking of key proteins and lipid messengers to critical destinations within the cell. Without intracellular transport mechanisms, cells cannot function properly. Because intracellular trafficking is essential for all cells, we set out to discover ways to cripple tumor cells by blocking ARF6. We have previously reported that activation of ARF6 promotes invasion and metastasis of melanoma. We also showed that ARF6 is abnormally activated in human melanoma and that pharmacologic inhibition of ARF6 activation reduces metastasis of melanoma. More recently, we learned that the development of melanoma is crippled by removing ARF6 in melanocytes, the normal pigmented cells of the skin that give rise to melanoma. Deletion of ARF6, specifically in melanocytes, significantly reduces tumor formation and slows the growth of BRAF-mutant melanoma. Because of this discovery, we are now studying the Fiscal Year 2021 (FY21) Melanoma Research Program (MRP) Focus Area of impeding the initiation and progression of primary melanoma … to prevent melanoma earlier in the disease cycle thus preventing metastasis. Our preliminary results suggest that loss of ARF6 in melanoma sensitizes tumor cells to immune attack and/or elicits an anti-tumor immune attack to suppress tumor formation and growth. This remains to be proven by the studies we have proposed herein but if true, we may have identified a new vulnerability in cancer that could be exploited to help eradicate melanoma in the early stages of development, preventing distant spread. Our proposed study will address the FY21 MRP challenge statement to identify how the tumor immune microenvironment impacts tumor initiation, progression and response to therapy. Specifically, we will effectively determine if loss or inhibition of ARF6 will (1) render melanoma more vulnerable to direct immune attack, (2) prevent tumor cells from releasing proteins that convert the immune system from anti-tumor to pro-tumor, and (3) improve melanoma responses to systemic immunotherapy (i.e. immune checkpoint blockade). Importantly, immune checkpoint blockade therapy is under investigation for early stage, non- metastatic melanoma (clinicaltrials.gov, NCT03553836 and NCT03757689). Thus, our work is timely, highly clinically relevant, may yield new insights into immune evasion mechanisms of early stage melanoma and identify new approaches for improving responses to systemic immunotherapy in these patients. We have specifically designed our studies to include disease models that represent dual populations of melanoma patients: (1) those likely to experience at least a partial response to immunotherapy and (2) those unlikely to respond at all. The two distinct models will allow us to test whether inhibition of ARF6 is effective in a broad range of patients, improving outcomes in the fraction of patients who receive benefit from immunotherapy and, hopefully, converting non-responders to responders.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210910
Entities
People
- Allie Grossmann
Organizations
- United States Army
- University of Utah