Professor Duke University, Department of Neurosurgery Durham, North Carolina, United States
Disclosure(s):
Joshua Jackson, MD, PhD: No financial relationships to disclose
Introduction: Glioblastoma (GBM) remains among the most fatal cancers with few treatment modalities and resistance to modern immunotherapeutic treatment paradigms including immune checkpoint inhibitors (ICI). ICIs neutralize the regulatory signals that disable T cells and have demonstrated remarkable efficacy against a variety of cancers, though not in GBM. The impotence of ICI in GBM has been linked to the tumor’s remarkable capacity to elicit T cell exhaustion, though the mechanism remains poorly understood. Chronic interferon (IFN) cytokine signaling is known to promote immunosuppression and Tex in several cancer types as well as resistance to ICI. However, the role of IFN in GBM has not been investigated despite evidence that IFN signatures exist within clinical samples of GBM.
Methods: Syngeneic murine GBM cell lines CT2A and SB28 were utilized for in vivo and in vitro studies Intracranial and subcutaneous injections were performed in the standard fashion. Anti-mouse PD-1, 4-1BB, and CD8 antibodies or PBS control were injected intraperitoneally. CRISPR editing was used to create validated knockouts (KO) of the type I IFN receptor (IFNAR1) in CT2A. Flow cytometry was validated and performed with murine-specific antibodies. Statistical analysis was performed in GraphPad with significance levels of 0.05.
Results: Mice bearing IFNAR1 KO intracranial tumors have a CD8 T cell-dependent extension of median survival. IFNAR1-KO tumors are also exquisitely sensitive to checkpoint blockade with anti-PD1 and anti-4-1BB. Mice bearing extracranial IFNAR1-KO tumors and treated with anti-PD1 frequently reject flank tumors and subsequently reject intracranial tumor challenge. Ongoing studies implicate the delay in developing the terminal T cell exhaustion phenotype as the mechanism behind these observations. All observations were found to be statistically significant.
Conclusion : Type I IFN signaling with GBM cells promotes T cell exhaustion in mice bearing GBM. Abrogation of Type I IFN signaling is sufficient to extend survival which is further enhanced by ICI. Work is ongoing to further elucidate the precise mechanism that mediates this response and to identify a therapeutic intervention that enables tumor-specific inhibition of the IFN pathway.
