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NIH grant 1R21CA318065-01: Development of spatial B cell antigen mapping to resolve TLS function in pancreatic cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Sophia Liu. Award: $415748.
Start: 2026-09-11T00:00:00.
PROJECT SUMMARY/ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers, with a five-year
survival rate under 15% and limited therapeutic options. A striking but unresolved feature of PDAC is the
presence of tertiary lymphoid structures (TLSs), ectopic immune aggregates that resemble germinal
centers and have been linked to improved prognosis and responsiveness to immunotherapy in many
other cancers. In PDAC, however, TLSs emerge early in precursor pancreatic intraepithelial neoplasias
(PanINs) and persist into invasive disease, yet they appear ineffective in promoting durable antitumor
immunity. Why TLSs sometimes promote tumor control while in other cases permit immune escape
remains a fundamental and unanswered question. A central barrier to progress is the inability to
determine B cell antigen specificity in situ. Current spatial transcriptomic platforms can recover B cell
receptor (BCR) sequences and clonal architecture, but they cannot identify cognate antigens.
Dissociative methods can link BCRs to antigens, but the spatial and organizational context of TLSs is lost
in the process. Without technologies that preserve both antigen specificity and tissue context, it is
impossible to define whether TLSs mount tumor-specific immune responses, react to bystander antigens,
or facilitate immune evasion In Aim 1, we will engineer DNA-barcoded antigen libraries compatible with
spatial transcriptomic arrays, validating the system in the well-established HEL/MD4 mouse model before
expanding to a PDAC-focused antigen panel. Animal models are required for these studies because the
HEL/MD4 system provides a controlled setting with defined B cell antigen specificity in tissues that cannot
be replicated in vitro, enabling validation of antigen detection accuracy and sensitivity prior to application
in human tissues. In Aim 2, we will apply spatial BCR sequencing and transcriptome profiling to frozen
PanIN and PDAC specimens to define B cell clonal evolution and TLS organization, and, where feasible,
integrate antigen mapping to determine whether TLSs harbor tumor-specific, bystander, or immuneevasive
responses. Importantly, even without antigen mapping, these analyses will yield high-value
insights into TLS clonal architecture, maturation states, and their relationship to disease progression. The
significance of this work is twofold. First, it will establish a generalizable platform capable of resolving B
cell antigen specificity, clonal identity, transcriptional program, and tissue location in intact tissue. Second,
it will apply this technology to PDAC, a cancer of urgent clinical need, thereby uncovering mechanisms
that may explain why TLSs support tumor control in some settings but fail in others. By combining
technological innovation with application to a pressing biological problem, this exploratory R21 project is
positioned to generate transformative insights into the role of TLSs in cancer progression.document fetched 2026-09-20 02:42