通过IFNβ依赖性抗肿瘤免疫反应提高了髓样细胞中删除TRIM33的效率
Deleting Trim33 in Myeloid Cells Improves the Efficiency of Radiotherapy through an IFNβ-Dependent Antitumor Immune Response
影响因子:8.20000
分区:医学1区 Top / 免疫学2区 肿瘤学2区
发表日期:2025 Jan 09
作者:
Anaïs Assouvie, Marine Gerbé-de-Thoré, Claire Torres, Véronique Ménard, Alexia Alfaro, Eric Deutsch, Michele Mondini, Germain Rousselet
摘要
放射疗法（RT）触发了有助于抗肿瘤作用的免疫反应。在RT的这种免疫原性中，IFNβ的诱导是关键事件。我们先前已经表明，TRIM33是一种染色质读取器，它可以限制Toll样受体激活的髓样细胞中的IFNβ表达。在这项研究中，我们探讨了在髓样细胞中删除TRIM33是否可以改善放射诱导的免疫反应和随后的RT效率。我们首先确定TRIM33 - / - 骨髓来源的巨噬细胞显示出对直接照射或用辐照癌细胞治疗的IFNβ的表达增加，从而进一步支持了我们的假设。然后，我们在三个皮下肿瘤模型和一个原位肿瘤模型中测试了单剂量RT的效率。在所有模型中，TRIM33的髓样缺失导致RT后的反应显着改善，从而在大多数带有原位口服肿瘤的处理过的小鼠中产生了完全耐用的反应。这种效应需要I型IFN途径的参与以及CD8+ T淋巴细胞的存在，而不是NK细胞。此外，固化小鼠能够拒绝次要肿瘤挑战，表明原位疫苗接种效应。我们得出的结论是，通过涉及I型IFN途径和免疫反应的机制，在髓样细胞中删除TRIM33可提高RT效率。我们的工作表明，髓样TRIM33是影响肿瘤对RT反应的宿主因素，因此代表了修饰RT反应的新潜在治疗靶标。
Abstract
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.