Melanoma Sequentially Suppresses Different DC Subsets in the Sentinel Lymph Node, Affecting Disease Spread and Recurrence

Mari F. C. M. van den Hout, Bas D. Koster, Berbel J. R. Sluijter, Barbara G. Molenkamp, Rieneke van de Ven, Alfons J. M. van den Eertwegh, Rik J. Scheper, Paul A. M. van Leeuwen, M. Petrousjka van den Tol, Tanja D. de Gruijl*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Web of Science)

Abstract

Melanoma exerts immune-suppressive effects to facilitate tumor progression and metastatic spread. We studied these effects on dendritic cell (DC) and T-cell subsets in 36 melanoma sentinel lymph node (SLN) from 28 stage I-III melanoma patients and determined their clinical significance. Four conventional DC subsets, plasmacytoid DCs, and CD4(+), CD8(+), and regulatory T cells (Tregs), were analyzed by flow cytometry. We correlated these data to clinical parameters and determined their effect on local and distant melanoma recurrence, with a median follow-up of 75 months. In stage I and II melanoma, increased Breslow thickness (i.e., invasion depth of the primary melanoma) was associated with progressive suppression of skin-derived migratory CD1a(+) DC subsets. In contrast, LN-resident DC subsets and T cells were only affected once metas-tasis to the SLN had occurred. In stage III patients, increased CD4: CD8 ratios in concert with the accumulation of Tregs resulted in decreased CD8: Treg ratios. On follow-up, lower frequencies of migratory DC subsets proved related to local melanoma recurrence, whereas reduced maturation of LN-resident DC subsets was associated with distant recurrence and melanoma-specific survival. In conclusion, melanoma-mediated suppression of migratory DC subsets in the SLN precedes local spread, whereas suppression of LN-resident DC subsets follows regional spread and precedes further melanoma dissemination to distant sites. This study offers a rationale to target migratory as well as LN-resident DC subsets for early immunotherapeutic interventions to prevent melanoma recurrence and spread. (C) 2017 AACR.

Original languageEnglish
Pages (from-to)969-977
Number of pages9
JournalCancer immunology research
Volume5
Issue number11
DOIs
Publication statusPublished - Nov 2017

Keywords

  • REGULATORY T-CELLS
  • DENDRITIC CELLS
  • INDOLEAMINE 2,3-DIOXYGENASE
  • METASTATIC MELANOMA
  • FUNCTIONAL-ANALYSIS
  • TUMOR BURDEN
  • IMMUNE
  • SKIN
  • ACCUMULATION
  • MULTICENTER

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