Abstract
ABSTRACTEvidence of tumor-resident mature B cell and antibody compartments and reports of associations with favorable prognosis in malignant melanoma suggest that humoral immunity could participate in antitumor defense. Likely striving to confer immunological protection while being subjected to tumor-promoting immune tolerance, B cells may engender multiple functions, including antigen processing and presentation, cytokine-mediated signaling, antibody class switching, expression and secretion. We review key evidence in support of multifaceted immunological mechanisms by which B cells may counter or contribute to malignant melanoma, and we discuss their potential translational implications. Dissecting the contributions of tumor-associated humoral responses can inform future treatment avenues.
Highlights
Evidence of tumor-resident mature B cell and antibody compartments and reports of associations with favorable prognosis in malignant melanoma suggest that humoral immunity could participate in antitumor defense
Investigations into the drivers of immune responses to melanoma elucidated a set of tumor-specific melanomaantigen-encoding gene families (MAGE, BAGE, GAGE), and several antigenic epitopes derived from human melanocyte lineage-specific proteins (MART-l/Melan-A, gpl[00], gp75 and tyrosinase) recognized by CD8C and CD4C T cells.[13,14,15]
Several personalized therapeutic approaches have been developed for melanoma involving adoptive cell therapy (ACT) with T cells.[21,22,23]
Summary
Rising incidence (global incidence reported in 2013 in 15–25 individuals in every 100,000) and the worst patient survival rates of all skin tumors continue to make malignant melanoma treatment clinically challenging, despite recent breakthroughs in targeted therapies.[1]. As tumor lesions bear characteristics consistent with chronic inflammation, the presence of tumor-associated TLS, which contain B cell infiltrates, reported in different tumor types including melanomas, may not be surprising.[37,45] In a study of 106 primary human melanoma lesions, 26% contained histologically visible aggregates.[37] Cipponi et al recovered and micro-dissected highly ordered TLS, defined as lymphoid follicles which contained clusters of B cells, follicular DCs, T cells and mature DCs from 7 out of 29 human melanoma metastases.[45] Sequencing of the immunoglobulin (Ig) repertoire of the lymphoid follicles revealed clonal amplification, isotype switching and somatic hypermutation, suggesting a local antigendriven response[45] (Fig. 1) These hallmarks of local B cell maturation have been observed in immunohistochemical analyses of extra-nodal TLS from human germ cell tumors[46] and breast carcinomas.[47] In an analysis of TLS in non-small cell lung cancer, characterization of B cell subsets by ONCOIMMUNOLOGY e1294296-3 immunohistochemistry and flow cytometry detected a prevalence of memory B cells and plasma cells producing tumor-specific antibodies, with the density of the follicle correlating with the number of mature plasma cells present.[48] In concordance, TLS were found to be prognostic of more favorable patient outcomes.[43,48]. These findings may indicate a role of TLS as local sites of B cell maturation, fostering the generation of in situ adaptive host immune responses
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