B cells and the humoral response in melanoma: The overlooked players of the tumor microenvironment

Abstract

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. 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.

Keywords: Antibodies; B cells; humoral response; immunoglobulins; immunosurveillance; melanoma; tumor microenvironment.

Figure 1.

Proposed B cell functions in the melanoma tumor microenvironment. B cells may arise from the local immune surveillance environment or migrate to the tumor from blood vessels. B cells may accumulate and expand in tumor-associated lymphoid structures (TLS), where they can encounter APCs and T cells, and undergo affinity maturation and clonal amplification. Within the tumor, plasma cells can secrete tumor-specific IgG1 antibodies, effective in inducing ADCC, ADCP and complement-mediated cytotoxicity. On the other hand, in the tumor microenvironment, B cells can be differentially activated to secrete antibody isotypes such as IgA, IgG2 and IgG4, which may induce a weaker immune response through (a) inability to activate the complement cascade, (b) lower affinities for activatory FcRs, (c) higher affinities for inhibitory FcRs, (d) lower potency in triggering ADCC and ADCP compared with IgG1 isotype antibodies and (e) in the case of IgG4, Fab-arm exchange, resulting in antibodies with low antigenic affinity. The tumor microenvironment may also differentially polarize B cells toward a regulatory phenotype (Breg) through the secretion of soluble factors such as IL-10, which, in turn, negatively influences immune cell activation and antibody class switching.

Figure 2.

Potential pro- and antitumor functions of tumor-infiltrating B cells. Tumor-infiltrating B cells may either promote or inhibit growth and metastasis through various immune mechanisms, involving secretion of antibodies, cytokine-mediated activation and recruitment of other immune effector cells and engagement and activation of T cells through antigen presentation via MHC in the presence of co-stimulatory molecules. Regulatory functions may be engendered through secretion of cytokines such as IL-10, T cell inhibition by PD-L1 expression or class switching and production of immunoglobulin isotypes with low immune effector stimulating functions.