epiglucan and Carcinoma--Pancreatic-Ductal

Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC.. β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag. IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE.. These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.

Topics: Animals; beta-Glucans; Carcinoma, Pancreatic Ductal; Electroporation; Mice; Pancreatic Neoplasms; Trained Immunity; Tumor Microenvironment

The prognosis in cases of pancreatic ductal adenocarcinoma (PDAC) with current treatment modalities is poor owing to the highly desmoplastic tumor microenvironment (TME). Herein, a β-glucans-functionalized zinc-doxorubicin nanoparticle system (βGlus-ZnD NPs) that can be orally administered, is developed for targeted PDAC therapy. Following oral administration in PDAC-bearing mice, βGlus-ZnD NPs actively target/transpass microfold cells, overcome the intestinal epithelial barrier, and then undergo subsequent phagocytosis by endogenous macrophages (βGlus-ZnD@Mϕ). As hitchhiking cellular vehicles, βGlus-ZnD@Mϕ transits through the intestinal lymphatic system and enters systemic circulation, ultimately accumulating in the tumor tissue as a result of the tumor-homing and "stealth" properties that are conferred by endogenous Mϕ. Meanwhile, the Mϕ that hitchhikes βGlus-ZnD NPs is activated to produce matrix metalloproteinases, destroying the desmoplastic stromal barrier, and differentiates toward the M

Topics: Animals; beta-Glucans; Carcinoma, Pancreatic Ductal; Macrophages; Mice; Pancreatic Neoplasms; Tumor Microenvironment

Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.

Topics: Animals; beta-Glucans; Carcinoma, Pancreatic Ductal; Humans; Kupffer Cells; Liver Neoplasms; Mice; Pancreatic Neoplasms