Cell 179, 1191–1206.e21 (2019)

Therapies that inhibit the immune checkpoint molecules PD-1 and CTLA-4 have demonstrated clinical success against ‘hot’, highly mutagenized tumors; however, triple-negative breast cancers (TNBC) have been less responsive. In Cell, Hollern et al. analyzed multiple mouse models of TNBC in response to combination anti-PD-1 plus anti-CTLA-4 therapy to identify predictive biomarkers in responsive tumors. They find that pretreatment covariant signatures indicative for follicular T helper (TFH) cells and B cells correlate with reduced tumor burden and increased survival upon combination therapy with immune checkpoint inhibitors. Similar TFH–B cell covariant signatures can be observed in human solid tumors. They show that clonally activated B cells within the tumor environment contribute as antigen-presenting cells and antibody-producing IgG+ cells. Depletion of either B cells, CD4+ T cells or the cytokine IL-21 diminishes the antitumor response to checkpoint blockade, demonstrating a role for B cells upon checkpoint blockade.