Background Glioblastoma is the most common primary brain tumor in adults with a median overall survival between twelve to fifteen months.^1,2 The prognosis is worse for patients older than 65 years of age.³Aging is associated with senescence, which leads to secretion of proinflammatory cytokines and increased levels of the immunosuppressive enzyme indoleamine-2,3-dioxygenase 1 (IDO1).⁴ Increased levels of IDO1 at an advanced age may attenuate the efficacy of immunotherapy.

Materials and Methods One hundred and seven mice between 79 and 92 weeks of age with differential Ido1 expression were intracranially injected with syngeneic murine GL261 cells and treated with PD-1 monoclonal antibodies and radiotherapy. The mice have been monitored for ninety days. U87 glioblastoma cells were cultured and treated with interferon-γ and NU223612.

Results PD-1 blockade and irradiation were less effective when Ido1 expression was preserved. Mouse lines with Ido1 knockout in dendritic and endothelial cells had better survival. There was a higher senescent cell burden within the brain tumor than the extra-tumoral tissue in mice reaching the humane endpoint. In U87 glioblastoma cells, interferon-γ induced upregulation of PD-L1 and IDO1 in a similar pattern. IDO1 degradation resulted in concomitantly lower levels of PD-L1.

Conclusions Taken together, these results suggest that the treatment protocol with PD-1 pathway blockade plus radiotherapy should be combined with IDO1 inhibitors and potentially with senolytics to achieve a better therapeutic outcome in the elderly population with glioblastoma.

References

1. Wen PY, Kesari S. Malignant gliomas in adults. New England Journal of Medicine 2008 Jul 31;359(5):492–507.

2. Delgado-López PD, Corrales-García EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clinical and Translational Oncology 2016 Nov;18(11):1062–71.

3. Ladomersky E, Scholtens DM, Kocherginsky M, et al. The coincidence between increasing age, immunosuppression, and the incidence of patients with glioblastoma. Frontiers in pharmacology 2019 Mar 27;10:200.

4. Ladomersky E, Zhai L, Lauing KL, et al. Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma. Clin Cancer Res 2020 Oct 1;26(19):5232–5245.

Disclosure Information E. Asimakidou: None. A. Bell: None. P. Bommi: None. D. Wainwright: None.