Identifying the antigenic drivers of tertiary lymphoid structure formation in solid cancers 3205

Description Tertiary Lymphoid Structures (TLSs) are ectopic lymphoid structures, formed in the presence of inflammation/tumors and are niches for antigen drainage. TLSs provide tumor-adjacent compartments to support cognate interactions of T follicular helper (Tfh) and B cells, which facilitate antigen-specific, anti-tumor responses. The presence of TLSs in solid tumors is associated with favorable prognosis. Despite the widely recognized importance of TLSs in cancer, the mechanisms behind their formation are poorly understood. We hypothesize that this process is driven by tumor antigens, but in absence of the knowledge of the antigens, it is difficult to understand their contribution to TLS formation. We posited that knowing the tumor antigens recognized by Tfh cells in tumor-associated TLSs will reveal the processes that lead to TLS formation and influence therapeutic outcome. In a murine melanoma model, we observed that intraperitoneal injections of B16-OVA tumor cells led to TLS formation. Upon confirming tumor-infiltrating Tfh cells by flow cytometry, we used scRNAseq to identify clonally expanded Tfh TCRs. We are currently using our lab’s antigen discovery platform to identify the tumor antigens recognized by the expanded Tfh TCRs and are aiming to perform spatial transcriptomics to identify TLS-specific Tfh antigens. These studies will uncover whether TLS formation is driven by tumor antigens and provide novel diagnostic and therapeutic targets to modulate TLS formation.