Black raspberries suppress pancreatic cancer through modulation of NKp46⁺, CD8⁺, and CD11b⁺ immune cells

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a low survival rate (9%). Epidemiologic studies show that healthy dietary patterns enriched of fruits and vegetables lower the risk of PDAC. We previously showed that supplementing black raspberries (BRBs) to patients with colorectal cancer increased tumor-infiltrating NK cells and their cytotoxicity. We aimed to determine whether BRBs combat PDAC by modulating cancer immunity. NOD.SCID mice lacking T and B cells were injected with human Panc-1-Luc cells orthotopically, and immunocompetent Kras ^LSL.G12D/+ -Trp53 ^LSL.R172H/+ -Pdx-1-Cre mice were fed BRBs. Peripheral blood mononuclear cells (PBMCs) from PDAC patients were treated with butyrate, a microbial metabolite of BRBs. The absence of T and B cells did not dampen BRBs' anti-tumor effects in the NOD.SCID mice. In the Kras ^LSL.G12D/+ -Trp53 ^LSL.R172H/+ -Pdx-1-Cre mice, BRBs significantly prolonged survival (189 days versus 154 days). In both models, BRBs decreased tumor-infiltrating CD11b⁺ cells and the expression of IL-1β, sEH, and Ki67. BRBs also increased tumor-infiltrating NKp46⁺ cells and the expression of CD107a, a functional marker of cytolytic NK and CD8⁺ T cells. In Kras ^LSL.G12D/+ -Trp53 ^LSL.R172H/+ -Pdx-1-Cre mice, tumor infiltration of CD8⁺ T cells was increased by BRBs. Further using the PBMCs from PDAC patients, we show that butyrate decreased the population of myeloid-derived suppressor cells (MDSCs). Butyrate also reversed CD11b⁺ cell-mediated suppression on CD8⁺ T cells. Interestingly, there is a negative association between MDSC changes and patients' survival, suggesting that the more decrease in MDSC population induced by butyrate treatment, the longer the patient had survived. Our study suggests the immune-modulating potentials of BRBs in PDAC.