B cell subsets are associated with durable responses in distinct cancer types after immune checkpoint inhibition

B cells are a critical arm of the adaptive immune system. However, the impact of B cells and antibody responses on overall cancer survival remains understudied. Here, we report results from a prospective randomized phase 2 trial of 106 patients treated with immune checkpoint inhibitors (ICIs) and identify that B cell antibody responses are associated with exceptional complete responses to ICI in certain cancer types. To further dissect the impact of B cell subtypes, we generated a comprehensive single-cell RNA sequencing database of intratumoral B cells in 12 tumor types from 152 patients. We found a context-dependent role for B cells, in which they are beneficial in certain cancer types and potentially unfavorable in others, with germinal center and memory B cells enriched in favorable prognosis cohorts and immunoglobulin A-positive plasma cells enriched in unfavorable prognosis cohorts. Depletion of B cells using rituximab in patients before surgery affected intratumoral T cell frequency and diversity. Furthermore, we show that B cells improve long-term overall survival even when T cell infiltrates are already high, indicating that a coordinated dual-arm T cell and B cell adaptive immune response is key to long-term tumor control. Overall, these results demonstrate that B cells and antibody responses in the proper context play an important role in durable complete responses in multiple tumor types.