Evidence of Th2 polarization of the sentinel lymph node (SLN) in melanoma

Travis E. Grotz, James W Jakub, Aaron Mansfield, Rachel Goldenstein, Elizabeth Ann L Enninga, Wendy K. Nevala, Alexey A. Leontovich, Svetomir Nenad Markovic

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Melanoma has a propensity for lymphatogenous metastasis. Improved understanding of the sentinel lymph node (SLN) immunological environment may improve outcomes. The immune phenotype of fresh melanoma SLNs (n = 13) were compared to fresh control lymph nodes (n = 13) using flow cytometry. RNA was isolated from CD4<sup>+</sup> T cells of the SLN and control lymph node and assessed for Th1/Th2 gene expression pathways using qRT-PCR. In addition, VEGF expression was compared between primary melanoma (n = 6) and benign nevi (n = 6) using immunohistochemistry. Melanoma SLNs had fewer CD8<sup>+</sup> T cells compared to controls (9.2% vs. 19.5%, p = 0.0005). The CD8<sup>+</sup> T cells within the SLN appeared to have an exhausted phenotype demonstrated by increased PD-1 mRNA expression (2.2% vs. 0.8%, p = 0.004) and a five-fold increase in CTLA-4 mRNA expression. The SLN also contained an increased number of CD14 (22.7% vs. 7.7%, p = 0.009) and CD68 (9.3% vs. 2.7%, p = 0.001) macrophages, and CD20 B cells (31.1% vs. 20.7%, p = 0.008), suggesting chronic inflammation. RT-PCR demonstrated a significant Th2 bias within the SLN. In vitro studies demonstrated a similar Th2 polarization with VEGF treatment of control lymph nodes. The primary melanoma demonstrated strong VEGF expression and an increase in VEGFR1 within the SLN. Melanoma is associated with Th2-mediated “chronic inflammation,” fewer cytotoxic T cells, and an exhausted T cell phenotype within the SLN combined with VEGF overproduction by the primary melanoma. These immunologic changes precede nodal metastasis and suggests consideration of VEGF inhibitors in future immunotherapy studies.

Original languageEnglish (US)
JournalOncoImmunology
Volume4
Issue number8
DOIs
StatePublished - Aug 3 2015

Keywords

  • CD4 T cells
  • CD8 T cells
  • immunotherapy
  • inflammation
  • lymphocytes
  • melanoma
  • sentinel lymph node
  • Th2 polarization
  • VEGF

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

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