德克萨斯大学Padmanee Sharma团队在研究中取得进展。他们报道了TET2突变克隆造血增强巨噬细胞抗原呈递和改善实体瘤免疫检查点治疗。2025年10月16日出版的《癌细胞》发表了这项成果。

利用实体瘤小鼠的Tet2^+/mut CH骨髓嵌合体模型，课题组发现Tet2突变的骨髓细胞在肿瘤微环境中大量存在，并有助于改善对ICT的反应。在机制上，肿瘤内的Tet2^+/mut巨噬细胞作为免疫原性抗原呈递细胞，更有效地交叉初始CD8⁺ T细胞以响应IFNγ。在35,971例非小细胞肺癌患者和25,064例结直肠腺癌患者的人类队列中，Tet2突变CH与ICT改善的预后相关。本研究提出Tet2^+/mut抗原呈递巨噬细胞在形成抗肿瘤免疫中的作用，并确定Tet2突变CH作为实体瘤患者对ICT反应改善的潜在生物标志物。

据介绍，克隆性造血（CH）在20%以上的实体瘤患者中可检测到，并与预后恶化有关；然而，其在肿瘤免疫学和免疫检查点治疗（ICT）中的作用尚不清楚。

附：英文原文

Title: TET2-mutant clonal hematopoiesis enhances macrophage antigen presentation and improves immune checkpoint therapy in solid tumors

Author: Shelley Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W. Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared Gilliam, Milan Radovich, Padmanee Sharma

Issue&Volume: 2025-10-16

Abstract: Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of Tet2+/mut CH in mice with solid tumors, we found the Tet2-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2+/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8+ T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients and 25,064 colorectal adenocarcinoma patients, TET2-mutant CH is associated with improved outcome specifically with ICT. This study proposes a role for Tet2+/mut antigen presenting macrophages in shaping antitumor immunity and identifies TET2-mutant CH as a potential biomarker for improved response to ICT in patients with solid tumors.

DOI: 10.1016/j.ccell.2025.09.011

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00403-9