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BACKGROUND AND AIMS: °Õ³Ò¹óβ plays pleiotropic roles in pancreatic cancer including promoting metastasis, attenuating CD8 T cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent °Õ³Ò¹óβ inhibition has shown limited efficacy against pancreatic cancer in mice or humans.METHODS: We evaluated the °Õ³Ò¹óβ blocking antibody NIS793 in combination with either gemcitabine/n(ab)-paclitaxel or FOLFIRINOX chemotherapy in orthotopic pancreatic cancer models. Single-cell RNA-seq and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment.RESULTS: Blockade of °Õ³Ò¹óβ with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, as response to °Õ³Ò¹óβ blockade was preserved in CD8-depleted or RAG2-/- mice. °Õ³Ò¹óβ blockade decreased total αSMA+ fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA-seq on tumor cells sorted ex vivo revealed that tumor cells treated with °Õ³Ò¹óβ blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that °Õ³Ò¹óβ blockade increased chemotherapy-induced cell death in vivo.CONCLUSIONS: °Õ³Ò¹óβ regulates pancreatic cancer cell plasticity between classical and basal cell states. °Õ³Ò¹óβ blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with either FOLFIRINOX or gemcitabine/n(ab)paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.