Glioblastoma (GBM) is an aggressive brain
malignancy with a dismal prognosis. With emerging evidence to disprove brain-immune privilege, there has been much interest in examining
immunotherapy strategies to treat central nervous system (CNS)
cancers. Unfortunately, the limited success of clinical studies investigating
immunotherapy regimens, has led to questions about the suitability of
immunotherapy for these
cancers. Inadequate inherent populations of tumor infiltrating lymphocytes (TILs) and limited trafficking of systemic, circulating T cells into the CNS likely contribute to the poor response to
immunotherapy. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the
tumor. In this study we evaluated the ability of
GSK126, a blood-brain barrier (BBB) permeable small molecule inhibitor of EZH2, to reverse GBM immune evasion by epigenetic suppression of T cell chemotaxis. We also evaluated the in vivo efficacy of this drug in combination with anti-PD-1 treatment on
tumor growth, survival and T cell infiltration in syngeneic mouse models.
GSK126 reversed H3K27me3 in murine and human GBM cell lines. When combined with anti-PD-1 treatment, a significant increase in activated T cell infiltration into the
tumor was observed. This resulted in decreased
tumor growth and enhanced survival both in sub-cutaneous and intracranial
tumors of immunocompetent, syngeneic murine models of GBM. Additionally, a significant increase in CXCR3+ T cells was also seen in the draining lymph nodes, suggesting their readiness to migrate to the
tumor. Closer examination of the mechanism of action of
GSK126 revealed its ability to promote the expression of IFN-γ driven
chemokines CXCL9 and CXCL10 from the
tumor cells, that work to traffic T cells without directly affecting T maturation and/or proliferation. The loss of survival benefit either with single agent or combination in immunocompromised SCID mice, suggest that the therapeutic efficacy of
GSK126 in GBM is primarily driven by lymphocytes. Taken together, our data suggests that in
glioblastoma, epigenetic modulation using
GSK126 could improve current
immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the
tumor.