Spatially resolving B and Plasma cell clonal dynamics in cancer

Despite the clinical success of immunotherapy, many cancer patients lack optimal treatment options. B cells and B cell-derived plasma cells (PC) have recently emerged as promising, yet untapped, therapeutic targets.

Here, I propose to use cutting-edge, in-house developed, spatial transcriptomics-based approaches to systematically interrogate B/PC biology in tumor progression and immunotherapy responses.

B lineage cells are compelling anti-cancer targets because they: i) infiltrate tumors and associate with positive prognosis and immunotherapy outcome across cancers, ii) present antigen to T cells, and iii) express clonal heritable B cell receptors (BCR) that confer exquisite molecular specificity.

B cell receptors can be defined by sequencing, but these methods require tissue dissociation, which loses the location, and surrounding environmental cues, of tumor-infiltrating B/PC clones.

Discovering the B/PC ‘clonal niche’ could identify key factors that determine to what, where, and how B/PC clones respond, and harness these to boost anti-tumor immunity.

We recently developed a spatial transcriptomics-based technology (Spatial VDJ) and the associated computational pipelines to capture and reconstruct full-length BCRs directly in their native tissues.

Here, I propose to use Spatial VDJ, along with other state-of-the-art methods, to link tumor-associated B/PC clones to their molecular and cellular environment with the ultimate goal to provide new immunotherapy strategies.