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

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

doi:10.1158/2326-6066.cir-17-0110

Mari F.C.M Van Den Hout, Tanja D De Gruijl + Show 8 more

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https://doi.org/10.1158/2326-6066.cir-17-0110

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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 metastasis 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. Cancer Immunol Res; 5(11); 969-77. ©2017 AACR.

Highlights

The sentinel lymph node (SLN) is a pivotal site not just in terms of early metastasis and as the birthplace of antitumor immunity [1]
Work by Cochran and coworkers indicated that lymph nodes close to melanoma tumors were more immunologically compromised than more distal ones [1, 22, 23]. In their studies of melanoma SLN, they observed a reduction in the frequencies of paracortical dendritic cell (DC) as well as in the complexity of their dendritic processes. These studies were largely based on morphology and immunohistochemistry, providing a rough measure of DC frequency and activation status but not accurate differentiation between different DC subsets
Given the complex composition of the DC compartment in human lymph nodes [8, 9], we used multi-color flow-cytometric analyses to investigate melanoma-induced effects on different DC and T-cell subsets. Combining this analysis with the AJCC melanoma staging system, we identified a stepwise pattern in which the primary melanoma first suppresses skin-derived DC subsets

Summary

Introduction

The sentinel lymph node (SLN) is a pivotal site not just in terms of early metastasis and as the birthplace of antitumor immunity [1]. Its importance is clear for melanoma, being one of the most immunogenic tumors [2,3,4]. The SLN is the most probable site for early metastasis, and the location where melanoma (neo-)antigens first drain and melanoma-derived antigen-presenting cells (APC) first migrate. It is the site where melanoma antigens are first presented to the na€ve immune system and the critical initial decision between activation and tolerance is made. The spread of melanoma through the lymphatic system may be facilitated. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

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