Sickle cell disease induces chromatin introversion and ferroptosis in CD8+ T cells to suppress anti-tumor immunity

IF 25.5 1区医学 Q1 IMMUNOLOGY

Immunity Pub Date : 2025-05-12 DOI:10.1016/j.immuni.2025.04.020

Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Jun Yao, Lanxin Bei, Yaohua Zhang, Pengju Gong, Lisa A. Huang, Zhou Jiang, Jian Gao, Shuang Peng, Tina K. Nguyen, Menuka Karki, Bora Lim, Cassian Yee, Jared K. Burks, Qing Zhang, Li Ma, Jianjun Gao, Chunru Lin

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Abstract

Understanding how genetic disorders affect CD8⁺ T cells in the tumor microenvironment is key to improving cancer immunotherapy. Individuals with sickle cell disease (SCD), the most prevalent inherited blood disorder, have a higher risk of developing certain cancers than the general population, but the mechanisms driving this increased risk remain unclear. Our study revealed that SCD altered CD8⁺ T cell 3D genome architecture, triggering ferroptosis and weakening anti-tumor immunity, thereby promoting tumor growth. Using murine and humanized SCD models, we found that disrupted chromosomal interactions in CD8⁺ T cells reduced the expression of anti-ferroptotic genes, including SLC7A11 and hydrogen sulfide (H₂S) biogenesis genes, thereby increasing susceptibility to ferroptosis. Therapeutic restoration of H₂S concentration in SCD mice rescued SLC7A11 expression, mitigated ferroptosis, and enhanced immune and anti-tumor responses. These findings highlight the impact of inherited disorders on cancer immunity and suggest precision immunotherapy strategies for affected individuals.

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镰状细胞病诱导CD8+ T细胞染色质内向和铁下垂抑制抗肿瘤免疫

了解遗传疾病如何影响肿瘤微环境中的CD8+ T细胞是改善癌症免疫治疗的关键。镰状细胞病（SCD）是最普遍的遗传性血液疾病，患有这种疾病的人患某些癌症的风险高于一般人群，但导致这种风险增加的机制尚不清楚。我们的研究表明，SCD改变CD8+ T细胞3D基因组结构，引发铁下垂，削弱抗肿瘤免疫，从而促进肿瘤生长。通过小鼠和人源SCD模型，我们发现CD8+ T细胞中染色体相互作用的中断降低了抗铁沉基因的表达，包括SLC7A11和硫化氢（H2S）生物发生基因，从而增加了铁沉的易感性。治疗性恢复H2S浓度可恢复SCD小鼠SLC7A11的表达，减轻铁下垂，增强免疫和抗肿瘤反应。这些发现强调了遗传性疾病对癌症免疫的影响，并为受影响个体提供了精确的免疫治疗策略。

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来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.