CTL-Tolerant Melanoma Persister Cells
Abstract
Fiscal year 2022 (FY22) Melanoma Research Program (MRP) Focus Area: We propose to characterize a novel population of melanoma cells which constitute dormant tumors and seed tumor recurrence. Therefore, this proposal addresses the FY22 MRP Focus Area: Delineate the molecular pathways that influence metastatic spread, recurrence, and/or dormancy. Melanoma tumors must escape the immune system in order to progress both during tumor initiation and also in the context of resistance to immunotherapy. If this process could be blocked therapeutically, melanoma progression would be prevented. However, we have limited understanding of how this process occurs. In particular, while we know that melanoma tumors can convert from initially immune reactive tumors into cold tumors in which immune cells are excluded or exhausted, we do not understand the mechanisms which govern this fundamental transition. In particular, the intermediate stage of this process, during which residual dormant melanoma cells survive immune attack and subsequently seed tumor regrowth, has proven very difficult to study. To study the dormant melanoma cells which survive immune attack, we have leveraged novel experimental models, which allow for observation of melanoma and immune cell interactions over prolonged timespans. Using these models, we made a profound discovery. We observed a novel population of dormant melanoma persister cells, which survive direct immune cell attack through unknown mechanisms. In addition, persister cells directly seed outgrowth of escaped melanoma cells which have acquired overt resistance to immune cells. Therefore, this proposal presents a new paradigm, centered around melanoma persister cells, for how melanoma tumors initially survive and then escape from the immune system. Therapeutic targeting of persister cells has the potential to prevent melanoma progression both during tumor initiation and acquired resistance to immunotherapy. Therefore, this proposal addresses the FY22 MRP Challenge Statement by revealing a new paradigm for melanoma immune evasion and progression which can be exploited to prevent melanoma progression. We propose to understand how persister cells form and survive immune attack, how persister cells seed outgrowth of immune cell-resistant melanoma cell populations, and to study the functional roles of persister cells in preclinical animal models of melanoma immunotherapy response. Together, these proposed aims will serve to provide the first characterization of this newly discovered melanoma cell population, which is critical for melanoma progression. This basic research has the potential to reveal new therapeutic targets within persister cells which may be utilized to prevent melanoma progression both during initial melanoma formation (e.g., neoadjuvant treatment) as well as during immunotherapy treatment (e.g., combination treatment) to prevent acquired resistance. Melanoma is among the most commonly diagnosed cancers in Service Members, Veterans, and other military beneficiaries, and while treatments for melanoma have advanced tremendously in the past decade, there remains a very strong need for new approaches to achieve durable treatment responses. This proposed work, by revealing a new population of melanoma cells which underlie immune resistance, has the potential to create a new field of research and an array of new therapeutic opportunities to prevent melanoma progression. Therefore, this proposal is appropriate in scope and impact for the MRP Idea Award.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310719
Entities
People
- Matthew Hangauer
Organizations
- United States Army
- University of California, San Diego