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.

Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy

“…The role of B cells in tumor immunology is still controversial at the moment and is related to positive and negative prognoses, respectively. However, evidence has been provided that a decline in B cell numbers is associated with irAE under ICI treatment of melanoma patients, in line with the results in the present study [ 40 ].…”

Systematic analysis of potential targets of the curcumin analog pentagamavunon-1 (PGV-1) in overcoming resistance of glioblastoma cells to bevacizumab

“…Another study showed that ADAM10 is involved in murine lupus progression on B cells ( Lownik et al, 2019 ). Moreover, B cells are key predictors of successful treatment in patients with melanoma, in which mature and differentiated B cells are directly correlated with checkpoint inhibitor drugs ( Willsmore et al, 2020 ). In addition, activation of B cells by a B cell based vaccine was shown to induce immunity toward glioblastoma ( Lee-Chang et al, 2021 ).…”

Germinal center hypoxia in tumor-draining lymph nodes negatively regulates tumor-induced humoral immune responses in mouse models of breast cancer

“…In our VHL fl/fl ;Cγ1 +/cre model, reduced GC formation in tumor-draining lymph nodes was associated with decreased T cell activation within 4T07 tumors, consistent with the emerging hypothesis that B cells may facilitate T cell activation during tumor-induced immune responses. 27 , 28 While it is possible that products of the GC reaction in lymph nodes, such as affinity matured BCRs and secreted antibodies, may modulate T cell activation in the lymph node or at the primary tumor site, it is notable that pVHL deletion in GC B cells only affected tumor-infiltrating T cell phenotypes in 4T07 tumors and not in 4T1 tumors. It is still unknown which conditions enable a T cell-promoting phenotype of B cells during anti-tumor immune responses, but it is plausible that some tumors fail to activate these functions in B cells and it is notable that 4T1 tumors are considered less immunogenic than 4T07 tumors.…”