Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors

Abstract

Glioblastoma multiforme is the most common and aggressive malignant brain tumor in humans and the prognosis is very poor despite conventional therapy. Immunotherapy represents a novel treatment approach, but the effect is often weakened by release of immune suppressive molecules such as prostaglandins. In the current study we investigated the effect of immunotherapy with irradiated interferon-γ (IFN-γ) secreting tumor cells and administration of the selective cyclooxygease-2 (COX-2) inhibitor parecoxib as treatment of established rat brain tumors. COX-2 inhibition and immunotherapy significantly enhanced the long-term cure rate (81% survival) compared to immunotherapy alone (19% survival) and there was a significant increase in plasma IFN-γ levels in animals treated with the combined therapy, suggesting a systemic T helper 1 immune response. COX-2 inhibition alone, however, did neither induce cure nor prolonged survival. The tumor cells were identified as the major source of COX-2 both in vivo and in vitro and unmodified tumor cells produced prostaglandin E 2 in vitro, while the IFN-γ expressing tumor cells secreted significantly lower levels. In conclusion, we show that immunotherapy of experimental brain tumors is greatly potentiated when combined with COX-2 inhibition. Based on our results, the clinically available drug parecoxib may be added to immunotherapy against human brain tumors. Furthermore, the discovery that IFN-γ plasma levels can be used to determine the ongoing in vivo immune response has translational potential.

Intratumoral COX‐2 inhibition enhances GM‐CSF immunotherapy against established mouse GL261 brain tumors

“…13,14 Furthermore, we previously reported that the combination of IFN-g immunotherapy and systemic COX-2 inhibition induced cure in rats with established intracerebral tumors. 15 Thus, the current study was undertaken to determine whether a GM-CSF-based immunotherapy was further enhanced by COX-2 inhibition. By applying different administration routes, we also assessed whether the therapeutic effect is dependent on the site of COX-2 inhibition.…”

Intratumorally implanted mesenchymal stromal cells potentiate peripheral immunotherapy against malignant rat gliomas

“…Immunotherapy per se induces an immune response associated with elevated plasma IFNγ levels and CD4 + and CD8 + T cells systemically and intratumorally (Visse et al, 2000;Eberstal et al, 2012;Fritzell et al, 2013a, b;Eberstal et al, 2014). IFNγ is predominately produced by activated T cells and thus, intratumorally implanted MSCs are most likely exposed to significant levels of IFNγ.…”

“…The cells have been transduced to express IFNγ (N32-IFNγ) (Visse et al, 1999) and both cell lines were cultured as described elsewhere (Eberstal et al, 2012).…”

Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy

“…Inhibition of MDSC accumulation was associated with elevated levels of CXCL10 and cytotoxic T lymphocytes in the TME [68]. Studies have looked at the efficacy of combining COX2 inhibitor celecoxib in combination with immunotherapy [119], dendritic cell vaccination [120], CD40 monoclonal antibody [121] with moderate to good success. GMCSF was upregulated in both human and mouse glioma TME and Kohanbash et al showed that GMCSF induced IL-4Rα expression on MDSCs in the glioma TME, that in turn induced arginase expression in response to IL-13 [80].…”