Pancreatic cancer chemotherapy is potentiated by induction of tertiary lymphoid structures in mice.

Abstract

BACKGROUND AND AIMS\nThe presence of tertiary lymphoid structures (TLS) may confer survival benefit to patients with pancreatic ductal adenocarcinoma (PDAC), in an otherwise immunologically inert malignancy. Yet, the precise role in PDAC has not been elucidated. Here we aim to investigate the structure and role of TLS in human and murine pancreatic cancer.\n\n\nMETHODS\nMulticolor immunofluorescence and immunohistochemistry was used to fully characterize TLS in human and murine (transgenic - KPC: KrasG12D, p53R172H, Pdx-1-Cre - and orthotopic) pancreatic cancer. An orthotopic murine model was developed to study the development of TLS and the effect of the combined chemotherapy and immunotherapy on tumor growth.\n\n\nRESULTS\nMature, functional TLS are not ubiquitous in human PDAC and KPC murine cancers and are absent in the orthotopic murine model. TLS formation can be induced in the orthotopic model of PDAC after intra-tumoral injection of lymphoid chemokines (CXCL13/CCL21). Co-administration of systemic chemotherapy (gemcitabine) and intra-tumoral lymphoid chemokines into orthotopic tumors altered immune cell infiltration facilitating TLS induction and potentiating anti-tumor activity of chemotherapy. This resulted in significant tumor reduction, an effect not achieved by either treatment alone. Anti-tumor activity seen after TLS induction is associated with B cell-mediated dendritic cell activation.\n\n\nCONCLUSION\nThis study provides supportive evidence that TLS induction may potentiate the anti-tumor activity of chemotherapy in a murine model of PDAC. A detailed understanding of TLS kinetics and their induction, due to multiple host and tumor factors may help design personalized therapies harnessing the potential of immuno-oncology.