在髓系细胞中敲除 Trim33 通过依赖 IFNβ的抗肿瘤免疫反应提高放疗效率

Radiotherapy (RT) triggers an immune response that contributes to antitumor effects. Induction of IFNβ is a key event in this immunogenicity of RT.

We have previously shown that TRIM33, a chromatin reader, restrains IFNβ expression in Toll-like receptor-activated myeloid cells. In this study, we explored whether deleting Trim33 in myeloid cells might improve the radio-induced immune response and subsequent efficiency of RT.

We first established that Trim33-/- bone marrow-derived macrophages showed increased expression of IFNβ in response to direct irradiation, or to treatment with irradiated cancer cells, further supporting our hypothesis.

We then tested the efficiency of a single-dose RT in three subcutaneous tumor models and one orthotopic tumor model. In all models, myeloid deletion of Trim33 led to a significantly improved response after RT, leading to a complete and durable response in most of the treated mice bearing orthotopic oral tumors. This effect required the involvement of the type I IFN pathway and the presence of CD8+ T lymphocytes but not NK cells.

In addition, cured mice were capable of rejecting a secondary tumor challenge, demonstrating an in situ vaccination effect.

We conclude that deleting Trim33 in myeloid cells improves RT efficiency, through a mechanism involving the type I IFN pathway and the immune response.

Our work suggests that myeloid Trim33 is a host factor affecting the tumor response to RT, thus representing a new potential therapeutic target for modifying RT responses.