Host STAT2/type I interferon axis controls tumor growth

Abstract

The role of STAT2 in mediating the antigrowth effects of type I interferon (IFN) is well-documented in vitro. Yet evidence of IFN-activated STAT2 as having tumor suppressor function in vivo and participation in antitumor immunity is lacking. Here we show in a syngeneic tumor transplantation model that STAT2 reduces tumor growth. Stat2−/− mice formed larger tumors compared to wild type (WT) mice. IFN-β treatment of Stat2−/− mice did not cause tumor regression. Gene expression analysis revealed a small subset of immunomodulatory genes to be downregulated in tumors established in Stat2−/− mice. Additionally, we found tumor antigen cross-presentation by Stat2−/− dendritic cells to T cells to be impaired. Adoptive transfer of tumor antigen specific CD8+ T cells primed by Stat2−/− dendritic cells into tumor-bearing Stat2−/− mice did not induce tumor regression with IFN-β intervention. We observed that an increase in the number of CD4+ and CD8+ T cells in the draining lymph nodes of IFN-β-treated tumor-bearing WT mice was absent in IFN-β treated Stat2−/− mice. Thus our study provides evidence for further evaluation of STAT2 function in cancer patients receiving type I IFN based immunotherapy.

STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross-Presentation

“…Studies show that TLR ligands induce DC-mediated cross-presentation in a MyD88-dependent manner (11, 18) but whether other signaling pathways are required for efficient cross-presentation remains unclear. We have recently published that Stat2 −/− cDCs, stimulated with LPS, are defective in tumor antigen cross-presentation in vitro and unable to stimulate anti-tumor Ag specific CD8 + T cells that indeed, upon adoptive transfer in vivo , failed to induce tumor regression (29). In the current study, we now confirm the defect of Stat2 −/− cDCs in cross-priming in vitro with a different Ag (Ovalbumin vs. Pmel-1).…”

“…A considerable body of literature underscores a prominent role for STAT2 in type I IFN-mediated antiviral (26, 27) and anti-tumor responses (28, 29). STAT2 is ubiquitously expressed in virtually all cell types.…”

“…We have recently published that Stat2 −/− cDCs are defective in cross-priming tumor Ag-specific transgenic CD8 + T cells in vitro . In addition, adoptive transfer of transgenic CD8 + T cells, who had been primed by these Stat2 −/− cDCs, into tumor bearing mice receiving IFNβ failed to cause tumor regression (29). These results indicate that STAT2 is important in anti-tumor immunity, but the cellular and molecular players of this immune response remain less known.…”

STAT2 (Signal Transducer and Activator of Transcription 2)

“…STAT2 is found to be decreased in many cancers including squamous cell carcinoma of the skin (Clifford et al, 2000;Clifford et al, 2002), fibrosarcoma (Krishnamurthy et al, 2006), astrocytomas (Ehrmann et al, 2008), melanoma (Mischiat et al, 2006), and prostate cancer (Ni et al, 2002). STAT2 has a tumor suppressor function (Clifford et al, 2002;Gamero et al, 2010;Yue et al, 2015) , though the mutations have not yet been identified in human cancer. To evade the antiviral protective effects of IFNs, certain viruses have developed strategies to impair the IFN signaling pathway by specifically targeting STAT2.…”

Interferon‑β sensitizes human glioblastoma cells to the cyclin‑dependent kinase inhibitor, TG02

“…IFN are endogenous cytokines that have a major role in combatting viral infections. Moreover, there is increasing interest in a role of type I IFN in suppressing tumor growth, notably a role in negatively regulating the cancer stem cell phenotype (8). We and others have previously characterized profound anti-glioblastoma stem cell properties of type I IFN in vitro that involved suppression of sphere formation but relatively little induction of cell death.…”