title: 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. 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.
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA.
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Ma
authors.forename: Ratna C
authors.initials: RC
authors.lastname: Medicherla
authors.forename: Meng
authors.initials: M
authors.lastname: Qian
authors.forename: Eleazar
authors.initials: E
authors.lastname: Vega-Saenz de Miera
authors.forename: Erica B
authors.initials: EB
authors.lastname: Friedman
authors.forename: Russell S
authors.initials: RS
authors.lastname: Berman
authors.forename: Richard L
authors.initials: RL
authors.lastname: Shapiro
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Shao
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D012372:ROC Curve; D021701:Sentinel Lymph Node Biopsy; D012878:Skin Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology*