微生物与免疫学学系Gregoire Lauvau研究小组揭示了MLL3突变通过HIF 1α依赖性瘤内募集和调节性T细胞分化促进乳腺癌进展。这一研究成果于2025年7月31日发表在国际顶尖学术期刊《免疫学》上。

为了研究MLL3抑制肿瘤发生的机制，研究人员建立了一个带有癌症驱动突变的多主题乳腺干细胞肿瘤模型，包括MLL3/KMT2C和p53的缺失以及组成型磷脂酰肌醇3-激酶（PI3K）的激活，概括了侵袭性人类乳腺癌的基因组成。MLL3缺失使转录因子HIF1α稳定，从而增加肿瘤细胞分泌趋化因子CCL2，促进CCR2⁺调节性T （Treg）细胞的募集。Treg细胞缺失减缓了肿瘤的发生和发展。在人类乳腺肿瘤中，Treg细胞的浸润与MLL3突变的存在相关。HIF1α使BLIMP-1依赖性肿瘤浸润Treg细胞分化为分泌免疫抑制因子转化生长因子β (TGF-β)和白细胞介素-10 （IL-10）的ICOS^hiGITR^hi效应细胞。针对ICOS或GITR的抗体可减少肿瘤Treg细胞并抑制肿瘤发生。因此，MLL3突变在侵袭性乳腺癌中形成了一种免疫抑制的肿瘤免疫微环境，也可能在功能性MLL3缺失的其他癌症中形成。

据悉，编码组蛋白甲基转移酶MLL3/KMT2C的MLL3的功能缺失突变在各种癌症类型中都很常见。

附：英文原文

Title: Mutations in MLL3 promote breast cancer progression via HIF1α-dependent intratumoral recruitment and differentiation of regulatory T cells

Author: Marie Boutet, Kenta Nishitani, Nicole Couturier, Piril Erler, Zheng Zhang, Anna Maria Militello, Marcelo Coutinho De Miranda, Emeline Barbieux, Erik Guillen, Jianmei W. Leavenworth, Masako Suzuki, Joseph A. Sparano, Jinyu Lu, Susan A. Fineberg, Yihong Wang, Sendurai A. Mani, Cristina Montagna, Wenjun Guo, Gregoire Lauvau

Issue&Volume: 2025-07-31

Abstract: Loss-of-function mutations in MLL3, encoding the histone methyltransferase MLL3/KMT2C, are frequent in various cancer types. To examine the mechanisms whereby MLL3 suppresses tumorigenesis, we developed a mouse mammary-stem-cell-based tumor model bearing cancer-driver mutations, including loss of MLL3/KMT2C and p53 and constitutive phosphatidylinositol 3-kinase (PI3K) activation, recapitulating a genetic makeup of aggressive human breast cancers. MLL3 loss stabilized the transcription factor HIF1α, which increased secretion of the chemokine CCL2 by tumor cells and promoted recruitment of CCR2+ regulatory T (Treg) cells. Treg cell depletion slowed tumor onset and progression. In human breast tumors, infiltration of Treg cells correlated with the presence of MLL3 mutations. HIF1α enforced BLIMP-1-dependent differentiation of tumor-infiltrating Treg cells into ICOShiGITRhi effectors that secreted the immunosuppressive cytokines transforming growth factor β (TGF-β) and interleukin-10 (IL-10). Antibody targeting of ICOS or GITR depleted tumor Treg cells and inhibited tumorigenesis. Thus, MLL3 mutations shape an immunosuppressive tumor immune microenvironment in aggressive breast cancers and likely in other cancers where functional MLL3 is lost.

DOI: 10.1016/j.immuni.2025.07.008

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00317-6