A blueprint for tumor-infiltrating B cells across human cancers
Jiaqiang Ma, Yingcheng Wu, Lifeng Ma, Xupeng Yang, Tiancheng Zhang, Guohe Song, Teng Li, Ke Gao, Xia Shen, Jian Lin, Yamin Chen, Xiaoshan Liu, Yuting Fu, Xixi Gu, Zechuan Chen, Shan Jiang, Dongning Rao, Jiaomeng Pan, Shu Zhang, Jian Zhou, Chen Huang, Si Shi, Jia Fan, Guoji Guo, Xiaoming Zhang, Qiang Gao
Abstract
B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.