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

• Published in: JCI insight 2019-09, Vol.5 (18)
• Main Authors: Garaud, Soizic, Buisseret, Laurence, Solinas, Cinzia, Gu-Trantien, Chunyan, de Wind, Alexandre, Van den Eynden, Gert, Naveaux, Celine, Lodewyckx, Jean-Nicolas, Boisson, Anaïs, Duvillier, Hugues, Craciun, Ligia, Ameye, Lieveke, Veys, Isabelle, Paesmans, Marianne, Larsimont, Denis, Piccart-Gebhart, Martine, Willard-Gallo, Karen
• Format: Article
• Language: English
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.129641

Tumor-infiltrating B-cells (TIL-B) in breast cancer (BC) have previously been associated with improved clinical outcomes; however, their role(s) in tumor immunity is not currently well known. This study confirms and extends the correlation between higher TIL-B densities and positive outcomes through an analysis of HER2-positive and triple-negative BC patients from the BIG 02-98 clinical trial (10yr mean follow-up). Fresh tissue analyses identify an increase in TIL-B density in untreated primary BC compared to normal breast tissues, which is associated with global, CD4+ and CD8+ 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 TFH TIL and antibody-secreting TIL-B principally located in tertiary lymphoid structures. Some TIL-B also interact directly with tumor cells. Functional analyses reveal TIL-B are responsive to BCR stimulation ex vivo, express activation markers and produce cytokines and immunoglobulins 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 generate effective anti-tumor immunity at the tumor site.