Chemokine-Extracellular Matrix Interactions as Drivers of Antimelanoma Immunity
Abstract
Scientific rationale: Drugs that target key points in the immune system have revolutionized the treatment of melanoma therapy. These therapies restore the activity of patient’s existing immune cells and promote anti-tumor activity. Although this is now standard of care for melanoma treatment, the majority of patients do not respond or have limited long-lasting benefit. Therefore, there is a critical need to understand how the tumor microenvironment determines the response to immunotherapy. A population of immune cells, known as stem-like memory cells, have enduring anti-tumor activity and are specifically activated during immunotherapy. Stem-like memory cells do not act in isolation, but as part of an immune network, both within tumors and in lymphoid tissue. How this immune network is organized and permitted by the tumor microenvironment is unknown. Recently, we have made a discovery that sheds light onto this question. Chemokines are small proteins that provide guidance cues for immune cells. By investigating how chemokines are deposited within the tumor and lymphoid tissue, we have identified a tumor-induced niche in each of these sites. We hypothesize that this chemokine niche specifically interacts with components outside of tumor cells to promote a coordinated anti-melanoma response. Objective and Aims: Our goal is to understand how the chemokine niche is established and maintained during melanoma induction and following immunotherapy. We will use advanced imaging to characterize the niche in a preclinical animal model and melanoma patient samples, investigating both the tumor and lymphoid organ involvement. Using a new model to disrupt chemokine: extracellular interactions, i.e., chemokine interactions with the components outside of cells, we will understand the impact of the chemokine niche on the potential to predict therapy response, anti-melanoma responses, tumor progression and identify the underlying molecular mechanisms of potent anti-melanoma activity. Innovation and Outcomes: We will combine powerful imaging and molecular analysis to reveal entirely new cellular and extracellular interactions and identify novel pathways to promote melanoma clearance. This project will provide first time proof that chemokine:extracellular interactions mediate the organization of melanoma- fighting immune cells and will launch new research to identify therapeutic strategies that target these interactions. Impact: This project will provide new knowledge to the scientific community, which will be used to advance melanoma research. In addition, it will significantly improve patient care by (1) providing essential information on the progression of disease for patients with melanoma to guide clinical management of patients, and (2) leading to new therapies that transform the tumor environment to promote ongoing anti-melanoma immune responses. These advances will be significant for those currently serving in the military or Veterans, since the incidence of melanoma is higher and the prognosis is poorer in this population in the United States. Ultimately, strategies that leverage chemokine:extracellular interactions have the potential to promote anti-melanoma regression as a single therapy, or to dramatically expand the number of melanoma patients that have long-lasting benefit from existing immunotherapies and increase their survival rates. Fiscal Year 2022 (FY22) Melanoma Research Program (MRP) Focus Area: Identify how the tumor microenvironment (e.g., stromal, immune, microbiome) impacts tumor initiation, response to therapy, progression, recurrence, and/or dormancy. This project will meet the MRP challenge by revealing how melanoma-flighting immune cells are maintained long-term to promote ongoing immunosurveillance and prevent tumor re-emergence.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310967
Entities
People
- Joanna Groom
Organizations
- United States Army
- WEHI