Diversification and shared features of tumor‐binding antibody repertoires in tumor, sentinel lymph node and blood of three patients with breast cancer

Abstract

Abstract Objectives B cell‐mediated immunity can be associated with favorable clinical outcomes in cancer patients. However, the mechanism and features of anti‐tumor immune responses are not well understood. In particular, how B cells expressing tumor‐specific antibodies are distributed (in the tumor vs. the circulation) has not been well defined. Methods We performed an in‐depth analysis of B cell antibody repertoires derived from the tumor, sentinel lymph nodes and peripheral blood of three treatment‐naïve patients with breast cancer. We integrated transcriptional analysis, next‐generation sequencing of immunoglobulin heavy‐chain gene rearrangements and phage display to define B cell responses and clonal architecture in the tumor microenvironment, and to identify antibodies against autologous tumor tissues. Results B cell clonal lineage mapping across sequencing libraries generated from the tumor, sentinel lymph node and blood revealed that some expanded B cell clones overlap between tumor and lymph node, and fewer clones overlapped with the peripheral blood. Notably, tumor‐associated or tumor‐binding clones recovered in the phage panning and tracked back through the tissues harboured extensive somatic hypermutations in both the tumor and the lymph node. Conclusions These findings suggest an evolving humoral immune response that targets the tumor and the possibility of monitoring B cell clones of interest in blood after identifying them in tumor or lymph node samples. Studying the dynamics and specificity of B cell responses may provide insights into the characteristics of successful anti‐tumor immunity, provide a means for monitoring therapy and yield novel targets for personalised therapies.

Keywords

• clonal selection
• humoral immunity
• lymph node
• tumor immunology