B cells and the coordination of immune checkpoint inhibitor response in patients with solid tumors

Abstract

Immunotherapy profoundly changed the landscape of cancer therapy by providing long-lasting responses in subsets of patients and is now the standard of care in several solid tumor types. However, immunotherapy activity beyond conventional immune checkpoint inhibition is plateauing, and biomarkers are overall lacking to guide treatment selection. Most studies have focused on T cell engagement and response, but there is a growing evidence that B cells may be key players in the establishment of an organized immune response, notably through tertiary lymphoid structures. Mechanisms of B cell response include antibody-dependent cellular cytotoxicity and phagocytosis, promotion of CD4+ and CD8+ T cell activation, maintenance of antitumor immune memory. In several solid tumor types, higher levels of B cells, specific B cell subpopulations, or the presence of tertiary lymphoid structures have been associated with improved outcomes on immune checkpoint inhibitors. The fate of B cell subpopulations may be widely influenced by the cytokine milieu, with versatile roles for B-specific cytokines B cell activating factor and B cell attracting chemokine-1/CXCL13, and a master regulatory role for IL-10. Roles of B cell-specific immune checkpoints such as TIM-1 are emerging and could represent potential therapeutic targets. Overall, the expanding field of B cells in solid tumors of holds promise for the improvement of current immunotherapy strategies and patient selection.

Keywords: B cell; Immune Checkpoint Inhibitors; Tumor microenvironment - TME.

Figure 1

BCR in solid tumors. (A) Coordination of the antitumor immune response by B cells. Antigen recognition by the B-cell receptor triggers a T cell-dependent or T cell-independent B cell response. The T cell-dependent response involves B and T-cell crosstalks within secondary or tertiary lymphoid structures. Interactions between B-cells and TFh through the CD40/CD40L axis allows for TFh activation, as well as initiation of a B cell germinal center reaction. Activation of TFh cells promotes T CD8+ activation and expansion in the T cell zone, ultimately prompting efficient T cell-mediated cytotoxicity. The germinal center reaction involves a positive selection of high-affinity, class-switched B cells that will differentiate into long-lived switched (IgG+) memory B cells or IgG+plasma cells. The humoral response exert antitumor effects through antibody-dependent cytotoxicity and phagocytosis. The T-independent response allows for swift generation of IgM+plasma cells or unswitched (IgM+) memory B cells, which harbor lower somatic hypermutation rates and lower antigen affinity compared with their switched (IgG+) counterparts; unswitched memory B cells have the ability to reinitiate a B-cell response and a germinal center reaction on repeated antigenic stimulation. (B) Modulation of the immune response by B cells. Tumor infiltration by regulatory B cells secreting immunosuppressive cytokines such as IL-10 allows for an immunosuppressive microenvironment. Immune complexes involving immunoglobulins and tumor antigens may promote activation of myeloid-derived suppressor cells. Complement activation by immunoglobulins may also promote MDSC activation and angiogenesis, inducing a protumoral microenvironment. BCR, B cell receptor Ig, immunoglobulin; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; TCR, T cell receptor complex; TFh, T CD4+ follicular helper.