Immunomodulatory antitumor effect of interferon‑beta combined with gemcitabine in pancreatic cancer

Abstract

Resistance to gemcitabine is common and critically limits its therapeutic efficacy in patients with pancreatic cancer. Interferon-beta (IFN-β) induces numerous antitumor effects and synergizes with gemcitabine treatment. The immunomodulatory effects of this treatment regimen have not yet been described. In the present study, the antitumor effect of IFN-β combined with gemcitabine was investigated in immune competent mice. Mouse KPC3 cells were used in all experiments. Treatment effects were determined with cell proliferation assay. Reverse transcription-quantitative PCR was used to measure gene expression. For in vivo experiments, cells were subcutaneously injected in immune competent mice. For immune profiling, NanoString analysis was performed on tumor samples of treated and untreated mice. Baseline expression of Ifnar-1 and Ifnar-2c in KPC3 cells was 1.42±0.16 and 1.50±0.17, respectively. IC 50 value of IFN-β on cell growth was high (>1,000 IU/ml). IFN-β pre-treatment increased the in vitro response to gemcitabine (1.3-fold decrease in EC 50 ; P<0.001). In vivo, tumor size was not statistically significant smaller in mice treated with IFN-β plus gemcitabine (707±92 mm 3 vs. 1,239±338 mm 3 in vehicle-treated mice; P=0.16). IFN-β alone upregulated expression of numerous immune-related genes. This effect was less pronounced when combined with gemcitabine. For the first time, to the best of our knowledge, the immunomodulatory effects of IFN-β, alone and combined with gemcitabine, in pancreatic cancer were reported. Prognostic markers for predicting effective responses to IFN-β therapy are urgently needed.

Oncolytic Adenoviruses Armed with Co-Stimulatory Molecules for Cancer Treatment

“…Yoshimura et al [ 110 ] reported that INF-β increased the anticancer effect in combined therapy with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) compared to TRAIL monotherapy. Blaauboer et al [ 111 ] showed that combining gemcitabine therapy with INF-β gives better results in vitro than monotherapy. However, INF-β loses its ability to promote the immunologic response of the cells after combining with gemcitabine.…”

Revisiting Circulating Extracellular Matrix Fragments as Disease Markers in Myelofibrosis and Related Neoplasms

“…In addition, IFN-alpha2 has also demonstrated a potent stem-cell-targeting potential by reactivating dormant JAK2V617F-positive stem cells and put them in cycle to be killed directly by IFN-alpha2 and IFN-activated immune cells (e.g., dendritic cells, NK-cells, T-cells) [240,241,244]. Interferon-beta (IFN-beta) has similar beneficial anti-cancer effects but is likely much stronger than IFN-alpha2, making it a potential alternative to IFN-alpha in the treatment of MPNs [452] and possibly also in the treatment of other cancers as well in combination with novel immunotherapies [453][454][455][456][457][458][459][460][461][462]. Remarkably, IFN-beta has been shown to suppress cancer stem cell properties in triple-negative breast cancer [460,461].…”