Public Defence: Adrian Eek-Mariampillai

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Trial Lecture – time and place

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Adjudication committee

• First opponent: Consultant Clinical Oncologist Magnus Dillon, The Institute of Cancer Research, UK
• Second opponent: Senior Research Specialist Kristina Viktorsson, Karolinska Institutet, Sweden
• Third member and chair of the evaluation committee: Professor II Kjersti Flatmark, University of Oslo

Chair of the Defence

Professor II Kristin Austlid Tasken, University of Oslo

Principal Supervisor

Scientst, Group Leader Randi G. Syljuåsen, Oslo University Hospital

Summary

Radiotherapy induces lethal DNA damage to cells, and is widely applied in cancer treatment. Nevertheless, cancers tend to develop radioresistance. Radioresistance may be counteracted by combining the irradiation with inhibitors of DNA repair. Additionally, the resistance may be overcome by increasing tumour immunogenicity.

Irradiation induces both immunosuppressive and -stimulatory effects in the tumour microenvironment. In his doctoral work in cancer radiobiology, Adrian Eek Mariampillai investigated whether the strategy of combining irradiation with DNA repair inhibitors increases the immunogenicity of human cancer cells. In particular, an inhibitor of ATR – a kinase regulating the G2/M cell cycle checkpoint – was employed, with the hypothesis that the co-treatment induces immunogenic cell death (ICD) and an interferon (IFN) response through cGAS-mediated detection of micronuclear DNA. It was also investigated how the co-treatment modulates presentation of the immune checkpoint ligand PD-L1.

By various molecular biology techniques, it was found that the co-treatment increased radiation-induced secretion of IFN-β and the ICD hallmarks ATP secretion and HMGB1 release. A third tested ICD hallmark, surface-presentation of calreticulin, was not increased. Interestingly, addition of a pan-caspase inhibitor increased the IFN secretion and to various extent also ATP secretion, whereas HMGB1 release was dependent on caspase activity.

It was also found that two histone deacetylase inhibitors (HDACi) evaluated in a previous DNA repair inhibitor screen increased radiation-induced presentation of PD-L1. The ATR inhibitor reduced the radiation-induced upregulation of PD-L1, but it did not alleviate the effect of the HDACi, meaning that two different mechanisms are involved. Finally, upregulation of PD-L1 was found to be cell cycle phase dependent.

Additional information

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