Establishing and Overcoming the Mechanisms of Liver Metastasis-Induced Systemic Tumor Immune Tolerance and Immunotherapy Resistance in Melanoma
Abstract
Melanoma inflicts both military personnel and civilians; however, Service Members are deployed for duty and training to locations of elevated risk from ultraviolet sunlight radiation. Once melanoma spreads, or metastasizes, to non-skin areas of the body, it substantially increases a patient’s chance of dying and causes the highest mortality among skin cancers. Recent advances revealed that our immune system can reject melanoma cells and be harnessed for treatment. However, less progress has been made in the prevention of the life-threatening melanoma dissemination, and most metastatic melanoma patients die from the disease despite modern immunotherapy known as checkpoint inhibitors (CPIs). This indicates a profound gap in our knowledge of melanoma immunity. To prevent lethal metastasis and intervene earlier at the initiation of its dissemination, we must understand of how the body’s immune defense against melanoma changes through disease progression. To that end, we propose to address the fiscal year 2022 (FY22) Melanoma Research Program (MRP) Focus Areas: (1) Identify how the tumor microenvironment (e.g., stromal, immune) impacts tumor initiation, response to therapy, progression, recurrence, and/or dormancy and (2) Delineate the molecular pathways that influence metastatic spread, recurrence, and/or dormancy. As outlined below, by studying how the liver’s exposure to melanoma cells from blood early in the disease process can contribute to disarming the entire body’s tumor immunity, our proposed research directly responds to the FY22 MRP Challenge Statement that to prevent melanoma progression, we must redefine prevention to include the entire melanomagenesis process and shift the paradigm of prevention to include inhibiting melanoma emergence from tumor dormancy and the development of metastases. Melanoma dissemination through blood early in the disease course. Evidence suggests distinct metastatic sites can have different immune responses. Recent studies suggest when melanoma spreads to the liver, as opposed to another organ, immunotherapy is less effective, bringing the CPI response rate from 40%-60% to less than 25%. This is concerning because the liver filters approximately 1.5 liters of circulating blood per minute and is under constant exposure to foreign proteins from the digestive system. The liver’s complex immune structure is capable of regulating our immune system to differentiate and ignore harmless food proteins or attack harmful pathogens (i.e., viral proteins). Although much has been learned about the permissive immune environment within the liver, how the liver shapes immunity outside the organ remains elusive. We hypothesize that when melanoma cells circulate to the liver, they could hijack the liver’s regulatory capabilities and reprogram our immune system to ignore, or tolerate, melanoma dissemination. This loss of immunosurveillance allows melanoma cells to wake from its dormancy unchecked, solidifying metastasis. Revealing the critical pathways will enable future strategies to prevent or contain life-threatening melanoma dissemination from dormancy. Our overall objective is to understand how the liver influences melanoma-specific immunity and design targeted interventions capable of reversing the immunosuppression. This includes the short-term goal of establishing the critical pathways responsible for liver-induced melanoma tolerance and the long-term goal of developing rationally designed precision approaches to reverse it. To accomplish our objectives, we plan to use our recently developed dual-tumor mouse model as an unique investigation tool into liver tolerance, which capture the unresponsive melanoma immunity in patients with liver metastasis by having tumors in both the skin and liver, allowing us to study how the liver impacts antitumor immunity at the distant site. Leveraging this model, correlated patient biospecimen data, and next-generation machine learning-driven
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310673
Entities
People
- Jimmie Ye
Organizations
- United States Army
- University of California, San Francisco