A DNA damage-induced immune response associated with tumour resistance

Project Code: 

Radiotherapy and chemotherapy are effective treatment methods for many types of cancer, but tumour resistance is common. We have recently discovered that these DNA damaging forms of cancer therapy lead to the release of single-stranded DNA (ssDNA) fragments from the cell nucleus into the cytosol of cancer cells, engaging this innate immune response (Erdal et al, Gene and Development, 2016, 31, p353-369). Furthermore, anti-viral type I interferon (IFN) signaling is induced by these treatments in cancer cells. The expression of a set of interferon-stimulated genes comprises the ‘IFN-related DNA damage resistance signature’ (IRDS) that correlates strongly with resistance to radiotherapy and chemotherapy across many tumour types. While classically, during viral infection, the presence of foreign DNA in the cytoplasm of host cells initiates type-I IFN production as part of the innate immune system, how self DNA is released from the nucleus of cancer cells during therapy to induce IFN signaling remains unknown. Moreover, it has recently become apparent that many tumors are inherently defective in specific DNA repair pathways and how these mutated repair pathways modify the response that engages IFN signaling will be investigated. This in turn will reveal new targets for future therapeutic intervention. Secondary supervision will be provided by Adrian Harris.

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