Characterizing human B-cell immune checkpoints to advance immunotherapy

B cells represent an attractive therapeutic target in autoimmunity, transplantation or cancer. However, the current B-cell-directed therapies rely mainly on non-selective pan-B-cell depletion with variable efficacy in different tissues and associated side effects, including severe infections. My preliminary data demonstrate that immune checkpoint molecules (ICMs)-key regulators of immune responses-are differentially expressed across human B-cell subsets and tissues. These findings open the opportunity for exploring B-cell heterogeneity, plasticity and avenues for more selective targeting. Using matched human tissue samples, state-of-art immuno-phenotyping technologies (including single-cell multi-omics, multi-parameter spectral flow cytometry, cytokines and antibody profiling), 3D immune organoid cultures (organ-on-chip) and multi-checkpoint CRISPR screens (Perturb-seq) and blocking antibodies, I will: (1) map baseline ICMs expression patterns across B-cell subsets in vivo, examining influences of tissue microenvironment, sex, and age to generate an integrated Human B-cell ICM Atlas; (2) characterize ICM expression dynamics during ex-vivo B-cell differentiation, expansion, and lymphoid follicle formation; (3) elucidate functional roles of ICMs in these biological processes. This work will deliver new insights into human B-cell biology necessary for developing more precise therapeutics with reduced toxicity, including advancement of future adoptive B-cell therapies. Additionally, it will illuminate potential mechanisms underlying autoimmune-like complications from checkpoint inhibitor therapies and inflammaging.