B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies

Abstract

The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation. Expressed antibodies may distinctly influence tumor regulation in the tumor microenvironment, with some isotypes associated with strong anti-tumor immune response and others with progressive disease. Recently, B cells have been evaluated in the context of cancer immunotherapy. Checkpoint inhibitors (CPIs), targeting T cell effector functions, have revolutionized the management of melanoma for many patients; however, there remains a need to accurately predict treatment responders. Increasing evidence suggests that B cells may not be simple bystanders to CPI immunotherapy. Mature and differentiated B cell phenotypes are key positive correlates of CPI response. Recent evidence also points to an enrichment in activatory B cell phenotypes, and the contribution of B cells to TLS formation may facilitate induction of T cell phenotypes required for response to CPI. Contrastingly, specific B cell subsets often correlate with immune-related adverse events (irAEs) in CPI. With increased appreciation of the multifaceted role of B cell immunity, novel therapeutic strategies and biomarkers can be explored and translated into the clinic to optimize CPI immunotherapy in melanoma.

Keywords: B cell; antibody; checkpoint inhibition therapy; humoral immune response; melanoma.

Figure 1

Proposed humoral responses in cancer and in response to checkpoint inhibitor immunotherapy. Putative pro- and anti-tumor roles of B cells in the tumor microenvironment (TME) and tumor tertiary lymphoid structures (TLS). B cells may confer several anti-tumor roles through production of effective tumor-clearing antibodies, predominantly IgG1: mediating antibody dependent cell-mediated cytotoxicity (ADCC), antibody dependent cell-mediated phagocytosis (ADCP) and facilitating complement activation. B cells can also effectively modulate CD4 and CD8 T cells via their functions as antigen presenting cells (APCs) to present tumor-derived antigens or by promoting cytokine secretion, particularly IFNγ and IL-2 by T cells. B cells can also support the presentation of tumor-derived antigens by other antigen presenting cells including macrophages and dendritic cells. Antigen presentation and B cell activation may be enhanced in TLS, leading to somatic hypermutation, clonal amplification and isotype switching to activatory antibody isotypes such as IgG1, further driving anti-tumor responses. B cells can also directly exert cytotoxic functions against tumor cells (e.g. through secretion of granzyme B). B cells can have pro-tumor roles by multiple mechanisms, for instance through expression of inflammatory antibody isotypes such as IgG4. IL-10 producing regulatory B cell (Breg) phenotype is described which can negatively modulate the function of effector CD8 T cells, induce the development of regulatory T cells (Tregs) and dampen the activity of antigen-presenting cells such as dendritic cells and macrophages. IgA producing regulatory B cells has also been described in the TME.

Figure 2

Proposed B cell features at baseline that predict response to checkpoint inhibitor treatment. B cell phenotypes enriched in tumors and the circulation of patients before treatment may be predictive of clinical response to checkpoint inhibitor therapy. Features include the presence of memory B cells (e.g. Ipilimumab monotherapy and combination of Ipilimumab and Nivolumab) and plasmablasts (e.g. Ipilimumab and Nivolumab monotherapies). In the peripheral blood, immunoglobulin isotypes IgG1, IgG2 and IgG3 have been associated with response to Ipilimumab and Nivolumab monotherapies. Melanoma-antigen specific IgG antibodies have been found to be increased in responders to therapy (monotherapy with Ipilimumab, Pembrolizumab and Nivolumab; as well as with combination of Ipilimumab and Nivolumab). Conversely, enrichment of tumors with IL10+ regulatory B cells and an absence of an IGHG gene signature have been associated with a poor response to Ipilimumab. FcγR, Fcγ receptor; NK, natural killer; TCR, T cell receptor.