GRANTS

The tumor microenvironment harbors diverse immune cell populations that influence patient prognosis and
response to immunotherapy. Recent findings highlight the significance of intratumoral B cells and CD4+ T
helper cells, particularly within tertiary lymphoid structures (TLSs). These ectopic lymphoid organs, which
resemble secondary lymph nodes, support B cell activation and antibody production, yet their role in tumor
immunity remains incompletely understood. Notably, T follicular helper (Tfh) cells drive B cell responses in
TLSs, but emerging evidence suggests that T peripheral helper (Tph) cells, a population not detected in
tumor mouse models, may also play a crucial role in boosting immune responses in tumors. Here, we aim to
generate a bispecific antibody, a B cell engager, that brings together Tph cells and B cells in tumors to boost
TLS formation and intratumoral immune responses.
First, we will characterize tumor-infiltrating human Tph cells in ovarian cancer using single-cell RNA
sequencing and spatial proteomics to define their transcriptional programs, location, and, most importantly,
novel surface receptors for future manipulations.
Next, we will design and evaluate a bispecific antibody targeting CD20 and PD-1 to promote Tph–B cell
interactions in vitro. Finally, we will assess its therapeutic potential in mouse models by investigating TLS
formation, immune cell activation, and tumor growth inhibition in vivo.
By leveraging Shulman's expertise in B cell immune responses and the Keren lab's cutting-edge multiplex
imaging and computational analyses, this research seeks to uncover novel mechanisms governing TLS
development and provide a translational pathway toward next-generation B cell engager immunotherapies.