Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

Abstract

In order to characterize the degree of immunosuppression in regional immunity in patients with melanoma, we used immunohistochemistry to analyze markers of T-cell subtype and polarity, costimulation, dendritic cell maturation, monocytes, lymphatic vasculature, and angiogenesis. Specifically, we analyzed expression of CD4, CD8, CD14, CD40, CD86, CD123, HLA-DR, IL-10, LYVE, VEGFR3, and VEGF-C in lymph nodes. We compared sentinel lymph nodes with and without metastasis from patients with melanoma with both infection inflamed (reactive) and dormant human lymph nodes. There were no differences demonstrated between sentinel lymph nodes with or without metastasis from patients with melanoma in any of the markers that were tested. Both groups of sentinel lymph nodes had fewer CD8 þ T cells than either set of control nodes. Whereas the infection inflamed lymph nodes demonstrated Th2 polarity, the dormant lymph nodes demonstrated Th1 polarity. In conclusion, changes in regional immunity appeared to precede metastasis in melanoma. Whether there was tumor present in sentinel lymph nodes or not, these nodes demonstrated a marked decrease in cytotoxic T cells compared with both sets of controls. Furthermore, the control lymph nodes used for comparison can significantly impact interpretation, as the dormant and reactive lymph nodes markedly varied in their immune profiles. These immunologic changes may explain the successful metastasis of melanoma in the midst of the immune environment of the sentinel lymph node, and lend insights into the mechanisms of lymphatic metastases in other solid malignancies. Modern Pathology (2011) 24, 487-494; doi:10.1038/modpathol.2010.227; published online 10 December 2010Keywords: angiogenesis; cytotoxic T cells; lymph nodes; melanoma; regional immunity Lymph node metastasis is one of the most important prognostic factors in melanoma.1 Whereas patients without nodal involvement generally have excellent outcomes, those with nodal involvement more commonly experience recurrence after resection and diminished survival. Previous investigations suggest that melanoma-draining lymph nodes demonstrate immunologic alterations and are likely immunosuppressed.2 Sentinel lymph nodes are the first lymph nodes to drain a tumor bed, and represent the first expected site of metastasis of melanoma.3,4 Sentinel lymph nodes are a site of contact between tumor-associated antigens and the adaptive immune system and represent a regional unit of metastasis and immune response. Accordingly, sentinel lymph nodes are an ideal setting for the investigations of the early immunologic (endocrine and paracrine) events that lead up to melanoma progression from a primary tumor to metastatic cancer. In the past year, we have described that patients with metastatic melanoma exist in a state of systemic chronic inflammation driven by tumorderived vascular endothelial growth factor (VEGF) overproduction leading to systemic immune polarization to a state of CD4 cell Th2 bias.5 Consequently, we sought to determine if similar differen...

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.…”

Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes – an immunohistochemical study

“…In melanoma patients it could be shown that tumor derived changes in the lymph node immune milieu are independent of the existence of lymph node metastases [14]. T-cell polarization and several immune tolerance markers did not differ between metastatic sentinel lymph nodes and tumor free nodes [49]. However, there are immunological alterations in tumor-associated lymph nodes that prepare them for the acceptance of tumor cells and are a prerequisite for metastatic tumor growth [14,49].…”

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

“…There was no difference in expression of these markers between SNs with and without metastases, suggesting that changes in regional immunity can precede metastasis. 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.…”