放射線が免疫細胞を腫瘍保護に変える仕組みと、その逆転方法を解明（Why do radiation cancer treatments sometimes fail? A new UChicago study suggests answers—and a solution）

2026-11-04

2026-11-02 シカゴ大学（UChicago）

米国シカゴ大学の研究チームは、がん放射線治療が一部の患者で十分な効果を発揮しない原因として、放射線によって免疫細胞が腫瘍を保護する状態に変化する仕組みを解明した。研究では、進行肺がん患者33人の治療前後の血液を分析し、骨髄由来抑制細胞（MDSC）で酵素TET2の発現が放射線照射後に増加することを確認した。TET2はRNAの化学修飾を除去し、インターフェロン関連遺伝子の働きを抑制することで、免疫細胞を免疫抑制型に変化させる。さらに、マウス実験ではTET2を阻害すると、MDSCが腫瘍抗原を提示して免疫細胞を活性化する新たな細胞群（MDAC）へと変化し、腫瘍の増殖や転移が抑制された。放射線治療とTET2阻害薬を組み合わせることで、免疫療法の効果も向上した。本成果は、放射線治療による免疫抑制を解除し、がん治療の効果を高める新たな治療戦略につながる可能性がある。

＜関連情報＞

骨髄系細胞のリプログラミングは、放射線療法の効果を高め、転移を抑制する骨髄由来活性化細胞を生成する Myeloid reprogramming generates myeloid-derived activating cells to potentiate radiotherapy and suppress metastasis

Fei Ji ∙ Lei Zheng ∙ Dapeng Chen ∙ … ∙ Hua Laura Liang ∙ Chuan He ∙ Ralph R. Weichselbaum
Cancer Cell Published: September 17, 2026
DOI:https://doi.org/10.1016/j.ccell.2026.08.017

Highlights

•RT-induced TET2 erases caRNA methylation, suppressing IFN pathway and immunity

•Tet2 inhibition and RT yield MDACs, an antigen-presenting myeloid subset

•MDACs are sufficient to restore antitumor CD8⁺ T cell immunity

•Myeloid reprogramming following Tet2 inhibition potentiates RT and immunotherapy

Summary

Radiation induces immunosuppressive myeloid cells that drive therapeutic resistance and metastasis. We identify TET2 as a radiation-induced regulator of myeloid-derived suppressor cells whose expression correlates with poor outcomes in advanced lung cancer patients receiving radio-immunotherapy. Following radiotherapy, myeloid-specific Tet2 deletion suppresses tumor progression and redirects monocyte differentiation toward antigen-presenting myeloid-derived activating cells (MDACs), which augment antitumor T cell responses; spatiotemporal mapping shows that this fate program initiates rapidly in the bone marrow. Mechanistically, a radiation-responsive p53-TET2 axis decreases m⁵C on chromatin-associated RNAs (caRNAs), enforcing immunosuppressive chromatin compaction and silencing interferon signaling, whereas Tet2 loss restores chromatin accessibility and enhances CD8⁺ T cell cytotoxicity. Pharmacological TET2 inhibition recapitulates this phenotype and augments radiotherapy and PD-L1 blockade to control primary and metastatic tumors. These findings define MDACs as an immunogenic myeloid subset and establish myeloid reprogramming as a strategy to improve radiotherapy-immunotherapy outcomes.

TET2によるRNA m5C酸化はクロマチン状態と白血病発生を制御する RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis

Zhongyu Zou, Xiaoyang Dou, Ying Li, Zijie Zhang, Juan Wang, Boyang Gao, Yu Xiao, Yiding Wang, Lijie Zhao, Chenxi Sun, Qinzhe Liu, Xianbin Yu, Hao Wang, Juyeong Hong, Qing Dai, Feng-Chun Yang, Mingjiang Xu & Chuan He
Nature Published:02 October 2024
DOI:https://doi.org/10.1038/s41586-024-07969-x

Abstract

Mutation of tet methylcytosine dioxygenase 2 (encoded by TET2) drives myeloid malignancy initiation and progression^1,2,3. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant haematopoietic stem cell self-renewal^4,5. However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukaemic cells and haematopoietic stem and progenitor cells⁵ is inconsistent with the designated role of DNA 5-methylcytosine oxidation of TET2. Here we show that chromatin-associated retrotransposon RNA 5-methylcytosine (m⁵C) can be recognized by the methyl-CpG-binding-domain protein MBD6, which guides deubiquitination of nearby monoubiquitinated Lys119 of histone H2A (H2AK119ub) to promote an open chromatin state. TET2 oxidizes m⁵C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. TET2 depletion thereby leads to globally decreased H2AK119ub, more open chromatin and increased transcription in stem cells. TET2-mutant human leukaemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocking proliferation of TET2-mutant leukaemic cells and largely reversing the haematopoiesis defects caused by Tet2 loss in mouse models. Together, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m⁵C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.

月	火	水	木	金	土	日
						1
2	3	4	5	6	7	8
9	10	11	12	13	14	15
16	17	18	19	20	21	22
23	24	25	26	27	28	29
30