Immune Profiling of Sentinel Lymph Nodes in Melanoma
Abstract
Two of the most important advances in melanoma in recent years have been the widespread application of lymphatic mapping/sentinel lymph node (SLN) biopsy and the development and approval of effective systemic therapies, including immunotherapy. The MRP Challenge Statement asks the research community to redefine the concept of progression, including examination of progression from the primary melanoma to metastases, evasion of the immune system and metastatic promotion. Our proposal focuses on the SLN, which is an absolutely critical site in disease progression and tumor-immune interactions. It is the most likely site for initial metastasis and the earliest site in which the melanoma and the immune system come into contact. This suggests that many of the fundamental characteristics of a patient’s anti-melanoma immune response are determined in the SLN. Using established, annotated clinical resources, we will examine the SLN with leading-edge laboratory techniques to produce exquisitely detailed information about tumor cells and immune cells in this critical location. We will use local biorepository protocols and resources derived from the second Multicenter Selective Lymphadenectomy Trial, the largest prospective melanoma clinical trial ever conducted. Our groups of study patients have been selected to maximize the power of the investigation, as detailed below. This work addresses MRP Focus Areas of the Tumor Microenvironment and Minimal Residual Disease (micro-metastases). The Aims of our proposal are derived from three clinical observations in melanoma treatment. SLN biopsy uses radioactive colloid tracers injected at the melanoma skin site just before surgery. These tracers are taken up and retained in SLNs, allowing identification of the nodes in the operating room. We have observed that the amount of tracer that is taken up in the nodes is inversely correlated with both patient age and survival. Our first aim examines the nodes of patients known to have high tracer uptake and those with low tracer uptake. We will identify the biological characteristics of the nodes that are responsible for this clinical observation and determine the immune mechanisms at work. This will lead not only to improved prognostic assessment of patients, but also to new avenues of treatment to overcome the deficits in patients with poor nodal uptake. For our second aim we will study variability in the patterns of progression in patients with melanoma. Some patients never progress, despite “high-risk” tumors. Some progress, but only ever to lymph nodes, and some show atypical progression to distant sites without showing melanoma in the lymph nodes. We have selected groups of patients who we know to have exhibited these progression patterns. We believe their lymph nodes contain critical information that can explain the behavior of their melanoma, which will relate to the immune competence of SLN, other lymph nodes, and their overall immune system. This will help identify targets beyond those for which we currently have treatments. Our final aim examines SLN in the context of checkpoint immune therapies. These revolutionary treatments can lead to durable remissions, even in late disease stages. However, they also fail in many patients. We believe the character of a patient’s immune response is set early in the course of their disease, likely in the SLN. We will investigate the immune microenvironment of SLNs of patients who received anti-PD-1 checkpoint inhibitors later in the course of their disease and compare patients who had a favorable response to therapy to those who did not. This can provide information that can predict who is most likely to respond to these treatments and identify new targets to improve outcomes in patients in the near future. Overall, this research will improve our understanding of how the immune system succeeds or fails at controlling melanoma and will point the way to new therapies for this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010632
Entities
People
- Mark Faries
Organizations
- Cedars-Sinai Medical Center
- United States Army