Plasma cells in primary melanoma. Prognostic significance and possible role of IgA

Abstract

Melanoma is not only one of the most immunogenic cancers but also one of the most effective cancers at subverting host immunity. The role of T lymphocytes in tumor immunity has been extensively studied in melanoma, whereas less is known about the importance of B lymphocytes. The effects of plasma cells (PCs), in particular, are still obscure. The aim of this study was to characterize pathological features and clinical outcome of primary cutaneous melanomas associated with PCs. Moreover, we investigated the origins of the melanoma-associated PCs. Finally, we studied the outcome of patients with primary melanomas with PCs. We reviewed 710 melanomas to correlate the presence of PCs with histological prognostic markers. Immunohistochemistry for CD138 and heavy and light chains was performed in primary melanomas (PM) and in loco-regional lymph nodes (LN), both metastatic and not metastatic. In three PM and nine LN with frozen material, VDJ-rearrangement was analyzed by Gene Scan Analysis. Survival analysis was performed on a group of 85 primary melanomas 42 mm in thickness. Forty-one cases (3.7%) showed clusters/sheets of PCs. PC-rich melanomas occurred at an older age and were thicker, more often ulcerated and more mitotically active (Po 0.05). PCs were polyclonal and often expressed IgA in addition to IgG. In LN, clusters/sheets of IgA+ PCs were found both in the sinuses and subcapsular areas. Analysis of VDJ-rearrangements showed the IgA to be oligoclonal. Melanomas with clusters/sheets of PCs had a significantly worse survival compared with melanomas without PCs while, interestingly, melanomas with sparse PCs were associated with a better clinical outcome (P = 0.002). In conclusion, melanomas with sheets/clusters of PCs are associated with worse prognosis. IgG and IgA are the isotypes predominantly produced by these PCs. IgA oligoclonality suggests an antigen-driven response that facilitates melanoma progression by a hitherto unknown mechanism.

Comprehensive histopathological comparison of epidermotropic/dermal metastatic melanoma and primary nodular melanoma

“…reported clusters of plasma cells in 22% of primary melanomas, a feature that was associated with increased Breslow thickness, ulceration, and poor survival . A recent study confirmed these associations, as well as higher mitotic activity . Interestingly, when found in metastatic melanomas, TIPs were reported to constitute a favourable prognosticator .…”

“…35 A recent study confirmed these associations, as well as higher mitotic activity. 36 Interestingly, when found in metastatic melanomas, TIPs were reported to constitute a favourable prognosticator. 37 Further investigation is needed to elucidate the immunological relationship between TIPs and melanoma cells.…”

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

“…Thereafter, we balanced the signal through dilution of the primary Abs to obtain staining levels and cell frequencies comparable to conventional immunofluorescence staining. The dilution of the CD19 antibody was optimized to allowing for the detection of CD19 low plasma cell-like cells as compared to patterns and frequencies obtained by CD138+ pooled IgA/IgG+ stainings on human tonsil and melanoma 17,19 . In multiplex stainings, single primary Ab stainings were run in parallel to control for false positive results through incomplete Ab-TSA complex-"stripping" and false negative results through antigen masking (by incubation with multiple primary Abs, "umbrella-effect").…”

“…In human cancer, Breg were described by either phenotyping, direct detection of immunoinhibitory cytokines or surface molecules, and/or immunosuppressive function 4,[9][10][11][12][13] .Often Breg frequencies increase with tumor progression and are enriched in tumors compared to peripheral blood or adjacent normal tissue. Increased IL-10 + B cell numbers can also be accompanied by increased numbers of CD4 + CD25 +/high CD127 low/and Foxp3 + Tregs in tumor tissues 10,12,14,15 which were independently associated with tumor progression or reduced patient survival.In human melanoma, up to 33% of the immune cells can be TAB 16,17 and phenotypic analysis has revealed CD20+ TAB (reviewed in 18 ) and CD138 + or IgA + CD138 + plasma cells 17,19 .Conclusions about their impact on disease progression and outcome are inconsistent. So far, no data exist for TAB functions in murine models of melanoma highlighting the need for studies in melanoma patients and tumor samples.…”

“…In human melanoma, up to 33% of the immune cells can be TAB 16,17 and phenotypic analysis has revealed CD20+ TAB (reviewed in 18 ) and CD138 + or IgA + CD138 + plasma cells 17,19 .…”