Suppression of Tregs by anti‐glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon‐α gene therapy for pancreatic cancer

Abstract

We have reported that interferon (IFN)-α can attack cancer cells by multiple antitumor mechanisms including the induction of direct cancer cell death and the enhancement of an immune response in several pancreatic cancer models. However, an immunotolerant microenvironment in the tumors is often responsible for the failure of the cancer immunotherapy. Here we examined whether the suppression of regulatory T cells (Tregs) within tumors can enhance an antitumor immunity induced by an intratumoral IFN-α gene transfer. First we showed that an intraperitoneal administration of an agonistic anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb), which is reported to suppress the function of Tregs, significantly inhibited subcutaneous tumor growth in a murine pancreatic cancer model. The anti-GITR mAb was then combined with the intratumoral injection of the IFN-α-adenovirus vector. The treatment with the antibody synergistically augmented the antitumor effect of IFN-α gene therapy not only in the vector-injected tumors but also in the vector-uninjected tumors. Immunostaining showed that the anti-GITR mAb decreased Foxp3+ cells infiltrating in the tumors, while the intratumoral IFN-α gene transfer increased CD4+ and CD8+ T cells in the tumors. Therefore, the combination therapy strongly inclined the immune balance of the tumor microenvironment in an antitumor direction, leading to a marked systemic antitumor effect. The CCR5 expression on Tregs was downregulated in the antibody-treated mice, which may explain the decrease of tumor-infiltrating Tregs. The combination of Treg-suppression by GITR mAb and the tumor immunity induction by IFN-α gene therapy could be a promising therapeutic strategy for pancreatic cancer.

Role of immune cells in pancreatic cancer from bench to clinical application

“…[139,140] Recently, antiglucocorticoid-induced TNF receptor monoclonal antibody has been introduced to suppress Tregs. Aida et al [47] showed this monoclonal antibody-induced suppression of Tregs infiltration in PC with down regulation of CCR5 and led to enhancement antitumor immunity of IFN-α gene therapy.…”

The New Era of Cancer Immunotherapy

“…Importantly, the success of therapy was seen in several tumor models, independently of tumor cell line sensitivity to NDV-mediated lysis, highlighting the importance of the virus-induced antitumor immunity rather than direct oncolysis in the observed therapeutic efficacy . A similar study using systemic agonistic anti-GITR antibody together with intratumoral administration of adenovirus expressing IFNα also resulted in synergistic inhibition of the virus-injected and distant tumors (Aida et al, 2014). Taken together, these studies thus provide a strong rationale for further evaluation of oncolytic viruses as potentiators of immunotherapy with agents targeting immune costimulatory or coinhibitory receptors.…”

Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors

“…Kavanagh et al observed that CTLA-4 blockade expanded Treg at low doses, but expanded effector T cells only at high doses [116]. Some studies have reported that anti-CTLA-4 or anti-GITR made effector T cells resistant to the inhibitory effect of Treg [44,117,118]. …”