B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome

Abstract

B cells are a major component of the tumour microenvironment, where they are predominantly associated with tertiary lymphoid structures (TLS). In germinal centres within mature TLS, B cell clones are selectively activated and amplified, and undergo antibody class switching and somatic hypermutation. Subsequently, these B cell clones differentiate into plasma cells that can produce IgG or IgA antibodies targeting tumour-associated antigens. In tumours without mature TLS, B cells are either scarce or differentiate into regulatory cells that produce immunosuppressive cytokines. Indeed, different tumours vary considerably in their TLS and B cell content. Notably, tumours with mature TLS, a high density of B cells and plasma cells, as well as the presence of antibodies to tumour-associated antigens are typically associated with favourable clinical outcomes and responses to immunotherapy compared with those lacking these characteristics. However, polyclonal B cell activation can also result in the formation of immune complexes that trigger the production of pro-inflammatory cytokines by macrophages and neutrophils. In complement-rich tumours, IgG antibodies can also activate the complement cascade, resulting in the production of anaphylatoxins that sustain tumour-promoting inflammation and angiogenesis. Herein, we review the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation as well as the potential of B cells and TLS as prognostic and predictive biomarkers. We also discuss novel therapeutic approaches that are being explored with the aim of increasing mature TLS formation, B cell differentiation and anti-tumour antibody production within tumours. The tumour microenvironment includes various diverse immune cell types, each of which might influence tumour progression and response to treatment, particularly with immunotherapies. These cell types include different subtypes of B lymphocytes, which are often associated with tertiary lymphoid structures (TLS) and can have pro-tumour or anti-tumour effects, either through their classical function in antibody production and antigen presentation or other mechanisms. Herein, Fridman et al. discuss the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation, the potential of B cells and TLS as prognostic and/or predictive biomarkers, and novel approaches aiming to enhance the development of TLS and anti-tumour B cells for cancer therapy.