Long-Term Protective Effect of Mature DC-LAMP+ Dendritic Cell Accumulation in Sentinel Lymph Nodes Containing Micrometastatic Melanoma

Abstract

Purpose: In a previous immunohistochemical study of dendritic cells (DC) in sentinel lymph nodes (SLN) draining regressing melanomas, we found that the accumulation of mature DC-LAMP + DCs in SLNs was associated with local expansion of antigen-specific memory effector CTLs and the absence of metastasis in downstream lymph nodes. The aim of this study was to investigate the prognostic importance of the maximal density of mature DCs in SLNs. Experimental Design: A total of 458 consecutive patients with micrometastatic melanoma within SLNs were eligible for analysis. The maximal density of mature DC-LAMP + DCs was evaluated by three independent observers and categorized into three classes (<100, 100 to <200, and z200/mm 2 ). Results: There was excellent interobserver reproducibility for maximum density of mature DC-LAMP + DC scores (j score = 0.82). There were differences in the maximal density scores and staining intensity according to the treating melanoma center (P < 0.001). The higher the mature DC density in the SLN is, the longer is the duration of survival [P = 0.047; hazard ratio, 0.70; 95% confidence interval, 0.50-1.00]. Adjusted by thickness and ulceration, the prognostic importance of DC density was lower (P = 0.36).Conclusion: This study is the first to report the prognostic value of DC-LAMP + DC counts in SLNs containing metastatic melanoma. Patients with a high density of mature DCs (z200/mm 2 ) have the lowest risk of death. It also provides evidence that a lack of maturation in the SLNs is important in biological facilitation of melanoma progression.

Distribution and Maturation of Skin Dendritic Cell Subsets in Two Forms of Cutaneous T-Cell Lymphoma: Mycosis Fungoides and Sézary Syndrome

“…Therefore, it is tempting to assume that their presence stimulates an anti-tumour immune response. This was confirmed in a more recent study that reported a significant correlation between the density of DC-LAMP* DC infiltrates in sentinel lymph node of melanoma patients with the absence of metastasis in downstream lymph nodes (38). Our observations therefore support the hypothesis of an ongoing anti-tumour immune response in MF lesions, leading to a prolonged disease course.…”

Dendritic cells matured by a prostaglandin E2-containing cocktail can produce high levels of IL-12p70 and are more mature and Th1-biased than dendritic cells treated with TNF-α or LPS

“…Furthermore, the MC-mDCs showed a significantly higher level of expression of LAMP3, PSCDBP, and CXCL16, in comparison to LPSmDCs and TNF-mDCs. LAMP3 is an important mDC marker, and accumulation of LAMP3 + mDCs was reported to be involved in induction of proliferation of memory effector CTLs and regression of metastatic melanoma (Elliott et al 2007), a Th1-type immune response. PSCDBP is an IL-12-induced gene in activated DCs and was reported to regulate DC-T cell adhesion by mediating DC-T cell de-attachment after antigen presentation (Hofer et al 2006) indicating a programmed change compatible with mDC characteristics.…”

The anticancer immune response: indispensable for therapeutic success?

“…Similarly, it could be important to preserve the sentinel lymph node rather than remove it systematically for disease staging purposes. Indeed, the sentinel lymph node constitutes the privileged site of antigen priming, in which the presence of activated DCs (expressing DC-LAMP - a protein only expressed in mature DCs) constitutes a positive prognostic marker, at least in melanoma (95).…”