Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node

Abstract

The sentinel lymph node is the initial site of metastasis. Down-regulation of anti-tumor immunity plays a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T-cells (Foxp3+) and dendritic cells (conventional: CD11c+, mature: CD86+) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunologic primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared to those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T-cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathologic variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Anti-tumor immunity was down-regulated in the positive sentinel lymph node with an increase in regulatory T-cells compared to the negative non-sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared to the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T-cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions.

Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression

“…This is the first study to analyze whole-genome gene expression profiling in SNB samples. Broad defects affecting different immunologic components have been extensively documented in SNs with respect to nontumor-draining nodes, including a decreased frequency of CD8 þ effector T cells, a reduced presence of stimulatory CD86 þ and CD11c þ DCs, and increased Foxp3 density and Th2 cytokine levels (7,11,(32)(33)(34)(35)(36)(37). Our findings partially contradict such observations because we found that immune dysfunction is detected in tumor-positive SNBs in association with disease progression.…”

Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma

“…Somatic immune indicators or molecular and cellular factors of immune response have been associated with melanoma progression, 92324 indicating that the balance of the immune repertoire (including tumour and effector T cell response, TILs or cytokine profiles) is important in modulating melanoma clinical outcomes. We hypothesise that genetic variation in the genes related to these processes may affect the immune capacity of the host.…”

Is Sentinel Node Susceptibility to Metastases Related to Nodal Immune Modulation?

“…56 A prospective study of Foxp3 + regulatory T cells and DCs in melanoma SNs showed correlations between node positivity and increased regulatory T cells or decreased dendritic cells. 57 Vallacchi et al, 58 using gene expression profiling of melanoma SNs and by unsupervised analysis of gene expression profiles, found "immune response" to be a major gene ontogeny represented.…”