Winning with the B team?

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Science Immunology  07 Feb 2020:
Vol. 5, Issue 44, eabb0236
DOI: 10.1126/sciimmunol.abb0236


The accumulation of B cells and tertiary lymphoid organs in metastatic melanoma patients receiving checkpoint blockade therapy was associated with long-term survival.

There have been several reported studies, in both human patients and murine models of cancer, that have linked B cells in either a positive or negative way to tumor outcomes. In one murine study, depleting B cells impaired tumor clearance. A triad of back-to-back reports, including Cabrita et al., now link an improved long-term outcome following checkpoint blockade therapy to the presence of tertiary lymphoid organs and B cells in melanomas and sarcomas. The authors show that in patients with metastatic melanoma, the presence of tertiary lymphoid structures and the co-occurrence of B cells with CD8+ T cells best correlate with an improved response to checkpoint blockade-based immunotherapy.

The associations between presence of TLOs and B cells with better tumor outcomes are convincingly shown in this and the companion studies. However, there is no evidence presented in these reports that indicate a mechanism. It may be that class-switched, somatically mutated, memory B cells in tumors present tumor antigens to helper T cells, which could be cytotoxic CD4+ T cells or helper T cells that facilitate the activation of CD8+ T cells. It is also theoretically possible that some hitherto uncharacterized activated B cell subpopulation can effectively cross-present antigens to CD8+ T cells and is therefore crucial in some tumor contexts. It is also conceivable that locally produced antibody to tumor antigens may facilitate the uptake of immune complexes by dendritic cells and therefore help in priming tumor-specific CD8+ T cells. However, another simple explanation for the data is that tertiary lymphoid structures and the B cells within are most likely an indirect correlate of the higher mutational burden (and therefore the immunogenicity) of certain tumors, but there is no direct or indirect protective role for B cells or tertiary lymphoid structures in clearing tumors. Any sufficiently antigenic lesion, be it linked to a pathogen or an unusually immunogenic or modified tumor-antigen, will invite in activated CD4+ T cells, CD8+ T cells, and B cells and facilitate the formation of tertiary lymphoid structures. Not all of the adaptive immune cells that enter an antigenic lesion are necessarily protective or pathogenic.

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