Immune Response in Melanoma

An In-depth Analysis of the Primary Tumor and Corresponding Sentinel Lymph Node

Michelle W Ma; Ratna C Medicherla; Meng Qian; Eleazar Vega-Saenz de Miera; Erica B Friedman; Russell S Berman; Richard L Shapiro; Anna C Pavlick; Patrick A Ott; Nina Bhardwaj; Yongzhao Shao; Iman Osman; Farbod Darvishian

Disclosures

Mod Pathol. 2012;25(7):1000-1010. 

In This Article

Abstract and Introduction

Abstract

The sentinel lymph node is the initial site of metastasis. Downregulation of antitumor immunity has 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/immunological 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 with 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, clinicopathological 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). Antitumor immunity was downregulated in the positive sentinel lymph node with an increase in regulatory T cells compared with 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 with 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.

Introduction

Sentinel lymph node status continues to be the most important prognostic factor in melanoma not only for recurrence[1] but also overall survival.[2,3] Melanoma patients with thick (>1.00 mm) and ulcerated primary tumors, in particular, are at high risk for occult nodal metastasis and warrant a sentinel lymph node biopsy to evaluate for the presence of nodal disease.[2] Sentinel lymph node metastasis, however, does occur in patients with thin (≤1.00 mm) melanomas[4] such that additional selection criteria may improve the sentinel lymph node positivity risk-stratification model based on thickness and ulceration alone.

Immune cell populations in the primary tumor reflect the host immune response, and there is evidence to suggest that the immunophenotype of this immune response is predictive of sentinel lymph node status not only in melanoma[3,5–10] but also in colorectal,[11] esophageal,[12] gastric,[13] and papillary thyroid cancer.[14] Primary tumor-infiltrating lymphocytes have an important role in the antitumor T cell response that mediates regression, and the absence of tumor-infiltrating lymphocytes and regression have both been shown to predict sentinel lymph node positivity in melanoma.[3,5–10] The prognostic relevance of different primary tumor T cell subsets, however, has not yet been examined in melanoma even though studies in other cancers have demonstrated the clinical value of characterizing tumor-infiltrating lymphocyte subpopulations, such as the immunosuppressive Foxp3+ regulatory T cell subset, in predicting nodal metastasis.[11–14] T cell responses, furthermore, require the antigen-presenting capacity of dendritic cells, including the immunogenic CD11c+ conventional dendritic cells and the tolerogenic CD123+ plasmacytoid dendritic cells. Dendritic cell subsets may therefore also predict sentinel lymph node positivity in melanoma, and one study in melanoma has already shown an association between primary tumor CD123+ plasmacytoid dendritic cells and clinical outcome.[15]

Primary melanoma immune markers warrant further investigation as potential predictors of sentinel lymph node status, and given the impact of primary tumor-derived cytokines on the immunological status of the sentinel lymph node[16] and the importance of the pathological status of the sentinel lymph node,[1–3] additional prognostic information may be gained by an immunological characterization of the sentinel lymph node as well. In this study, our objective was to first examine the relationship between the immune profile of the primary melanoma and sentinel lymph node positivity and then to compare the immunophenotype of the immune response in positive sentinel lymph nodes with that in negative sentinel lymph nodes and negative non-sentinel nodes from the same nodal basin and to correlate it with clinical outcome in a cohort of prospectively-accrued cutaneous melanoma patients.

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