删除髓系细胞中的Trim33通过依赖IFNβ的抗肿瘤免疫反应改善放疗效率

Deleting Trim33 in Myeloid Cells Improves the Efficiency of Radiotherapy through an IFNβ-Dependent Antitumor Immune Response

Cancer Immunology Research

影响因子:8.2

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

DOI: 10.1158/2326-6066.CIR-24-0026

摘要

放疗（RT）能激发免疫反应，增强抗肿瘤作用。诱导IFNβ是RT免疫原性的重要事件。我们此前发现，染色质阅读器TRIM33在 Toll 样受体激活的髓系细胞中抑制IFNβ的表达。本研究探讨在髓系细胞中删除Trim33是否能增强放疗引发的免疫反应及其治疗效果。首先，我们证实Trim33-/-骨髓来源巨噬细胞在直接照射或用辐射癌细胞处理后，IFNβ的表达增加，进一步支持我们的假设。随后，我们评估了单次剂量放疗在三种皮下肿瘤模型和一种原位肿瘤模型中的疗效。在所有模型中，髓系细胞中Trim33的缺失显著改善了放疗效果，在大部分接受放疗的正颌肿瘤鼠中实现了完全且持久的反应。这一作用依赖于Ⅰ型干扰素途径和CD8+ T淋巴细胞的参与，但不依赖于NK细胞。此外，治愈的动物能够拒绝二次肿瘤挑战，表明具有原位疫苗作用。我们得出结论：在髓系细胞中删除Trim33可以通过涉及Ⅰ型干扰素途径和免疫反应的机制，改善放疗效果。我们的研究提示，髓系细胞中的Trim33是影响肿瘤对放疗反应的宿主因素，可能成为改良放疗反应的新靶点。

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.