Impact and mechanisms of PD-L1, PD-L2 and EGF-R expression on glioma cells following radiochemotherapy and its consequences for combination with vaccination and PD-1 inhibition

• Applicant: Anja Derer, Ph.D.
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409923888

Patients diagnosed with highly malignant glioblastoma multiforme (GBM) have to face a very poor prognosis with a median survival rate of only about 15 months and a 95% recurrence rate, wherefore therapy improvements are urgently needed. Current therapeutic options include resection with subsequent radiochemotherapy with the aims to remove the main tumour bulk, to inhibit tumour cell proliferation and to induce tumour cell death. Over the last years mainly case-reports showed that systemic anti-tumour-immune responses can be achieved with radiotherapy (RT), however this is not a frequent event. Other research teams and we already demonstrated, that tumour cells can be rendered immunogenic by RT, but do also increase the expression of immune checkpoint molecules, as programmed death ligand 1 (PD-L1), which might counteract radiation-induced immune activation. Under normal physiological conditions PD-L1 suppresses T cell function in order to prevent from an overshooting T cell reaction and to maintain a healthy immune cell homeostasis. The objective of this proposal is to unravel the mechanistic background of the immunogenic potential of GBM tumour cells following not only RT but also radiochemotherapy (RCT) in particularly linked to the expression of the immune checkpoint molecules PD-L1 and PD-L2 as well as to Epidermal Growth Factor Receptor (EGF-R). We hypothesize that that the combination of (A) classical RCT for GBM (for killing and generation of primary immunogenic tumour cells) with (B) monoclonal anti-PD-1 antibody (for the suppression of tumorigenic immune escape mechanisms via PD-L1 and PD-L2) plus (C) a novel vaccination strategy for induction of a long-term immunological memory will improve both short term anti-glioma immune responses and help to reduce the extremely high recurrence rate of GBM. Thus, we seek to analyse glioblastoma tumour cells for PD-L1, PD-L2 and EGF-R surface expression after conventional RCT and to investigate their impact on lymphoid and myeloid cell-dependent immune responses. Mechanistic signalling pathway analyses of PD-L1, PD-L2 and EGF-R expression on GBM tumour cells after RCT will be conducted. Further, cellular mechanisms after experimental vaccination with autologous tumour cells generated by high hydrostatic pressure technology (HHP) in multimodal settings of RCT with PD-1 inhibition will be studied with the orthotopic GL261 mouse model. This work will contribute to a better understanding and optimization of multimodal radioimmunotherapy treatments for this fatal tumour disease.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr.-Ing. Benjamin Frey