Mechanisms of induction of type I/III interferons in cancer cells by ionizing radiation and the role of tumour cell-derived type I IFN and type I IFN signalling in anti-tumour immune response

Interferons (IFNs) are a group of cytokines that have been shown to play an important role in both radiotherapy and the anti-tumour immune response. How ionizing radiation (IR) induces IFNs in the tumour is still not fully understood. We found that IR directly induced dose- and time-dependent upregulation of I/III IFNs in cancer cells. This induction occurs via cytosolic DNA sensors-STING-TBK1-IRFs signalling axis and to less extent, the NF-κB pathway in colorectal cancer cells. Furthermore, Type I/III acts as a feedback loop to further enhance IFNs expression via upregulating key factors in the signalling axis. In vivo, cancer cells not the immune cells actually have the greatest contribution to overall intratumoural production of type I IFN in the MC38 tumours. By using a variety of animal models, we demonstrated that tumour-derived type I IFN has critical contribution to the anti-tumour immune response at local site. Strikingly and unexpectedly, abrogation of type I IFN signalling via IFNAR1 KO in cancer cells led to remarkable improvement of tumour response to IR. This phenomenon is mainly driven by significantly enhanced susceptibility of cancer cells to CD8+ T cellmediated killing via PD-L1/Galectin-9-independent mechanisms. Overall, these findings add another layer of complexity to the understanding of irradiation-induced anti-tumour immunity and cancer immune evasion, and may provide novel insights into combinational therapy of radiotherapy and immunotherapy.