Tumor-infiltrating B cells signal functional humoral immune responses in breast cancer

Tumor-infiltrating B cells (TIL-B) in breast cancer (BC) have previously been associated with improved clinical outcomes; however, their roles in tumor immunity are not currently well known. This study confirms and extends the correlation between higher TIL-B densities and positive outcomes through an analysis of HER2(+) and triple-negative BC patients from the BIG 02-98 clinical trial (10-year median follow-up). Fresh tissue analyses identify an increase in TIL-B density in untreated primary BC compared with normal breast tissues, which is associated with global, CD4(+), and CD8(+) tumor infiltrating lymphocytes (TIL); higher tumor grades; higher proliferation; and hormone receptor negativity. All B cell differentiation stages are detectable, but significant increases in memory TIL-B are consistently present. BC with higher infiltrates are specifically characterized by germinal center TIL-B, which in turn are correlated with T follicular helper (T-FH) TIL and antibody-secreting TIL-B principally located in tertiary lymphoid structures. Some TIL-B also interact directly with tumor cells. Functional analyses reveal that TIL-B are responsive to B cell receptor (BCR) stimulation ex vivo, express activation markers, and produce cytokines and Igs despite reduced expression of the antigen-presenting molecules HLA-DR and CD40. Overall, these data support the concept that ongoing humoral immune responses are generated by TIL-B and help to promote effective antitumor immunity at the tumor site.