Tumor-Draining Lymph Node B Cells as Regulators of Melanoma Progression
Abstract
This study is relevant to the military population and addresses the focus areas of “Minimal Residual Disease” and “Therapeutic Prevention.” The Fiscal Year 2019 Melanoma Research Program challenge statement aims to redefine the concept of melanoma prevention which is addressed in this study. Approximately 100,000 people a year are diagnosed with melanoma, including military personnel and Veterans. Although 90% of primary cutaneous melanoma is cured with surgery, recurrent metastatic disease contributes to high mortality rates. Thus, it is imperative to identify and stop melanoma disease progression prior to spread. Many patients that present with primary cutaneous melanoma undergo evaluation of tumor adjacent lymph nodes via sentinel lymph node (SLN) biopsy. Presence of tumor in the SLN is used as a predictor of tumor recurrence in melanoma patients. However, this methodology does not capture patients that recur despite lack of tumor in the SLN. As a result, patients with tumor in SLN are often over-treated while those that lack tumor are undertreated. We are in dire need of biomarkers that more reliably identify patients that are cured and accurately predict patients who need additional therapeutic treatments. B cell immune signatures are now emerging as potential predictor of disease outcomes in different solid tumors, including melanoma; however, these studies are limited. Our objective is to determine SLN B cell signatures that predict melanoma recurrence in patients that present with localized disease. This knowledge can then be used to not only stratify patients that will need further therapeutic treatment, but to also target B cell signaling pathways to improve patient outcomes and limit recurrence. The immediate impact of this work on melanoma patients is that successful completion of the proposed aims will provide proof-of-concept data and give clinicians a predictive biomarker beyond general clinical characterization to aid in therapy decision making. 70% of patients who present with tumor in their SLN do not recur and are therefore subjected to toxic systemic therapies that impact their quality of life. On the other hand, around 15% of patients with no tumor in the SLN will recur. However, due to lack of additional predictive factors, we are unable to identify this select group of patients that would benefit from neoadjuvant therapy. This proposal will examine the relevance of SLN B cells (signatures and signaling) as biomarkers that predict the ability of the host to induce long-lived anti-tumor immune responses and prevent disease recurrence. Moreover, these data will set the stage for future development of therapies that target the B cell axis of therapeutic treatment. In the long term, our hope is that this innovative approach will revolutionize melanoma clinical management and treatment options. Additional clinical trials will be required to establish and change how melanoma is managed prior to metastatic spread. This should lead to decreased health care cost and increased quality of life for afflicted patients and their families. Moreover, a better understanding of the B cell axis and the role that it plays in the melanoma disease control will provide us with additional therapeutic avenues, including combination therapies to induce antitumor immunity.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010808
Entities
People
- Eduarta K. Holl
Organizations
- Duke University
- United States Army