<br>焦亡巨噬细胞通过TLR4信号通路促进外周T细胞淋巴瘤的增殖和化疗耐药,Cancer Science

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焦亡巨噬细胞通过TLR4信号通路促进外周T细胞淋巴瘤的增殖和化疗耐药
Cancer Science ( IF 4.5 ) Pub Date : 2024-04-13 , DOI: 10.1111/cas.16180
Han Zhang ₁ , Liru Li ₁ , Zijian Zhang ₁ , Shiqi Gao ₁ , Mingzhe Yang ₁ , Wenjie Ma ₁ , Hongbin Li ₁ , Wenhui Zhao ₁ , Huike Yang ₂ , Yue Zhang ₁ , Shu Zhao ₁

Affiliation

外周T细胞淋巴瘤（PTCL）是一种高度侵袭性的非霍奇金淋巴瘤，预后较差。细胞焦亡是一种新发现的程序性细胞死亡模式，在肿瘤细胞和免疫细胞中都会发生。然而，焦亡对PTCL的发生和影响仍不清楚。在这里，我们发现焦亡发生在 PTCL 的间质巨噬细胞中，而不是肿瘤细胞中。在临床标本中，巨噬细胞焦亡与 PTCL 的不良预后相关。体外实验和基因测序结果表明，焦亡巨噬细胞可以通过分泌炎症细胞因子IL-18上调TLR4的表达。上调的TLR4激活其下游NF-κB抗凋亡信号通路，从而导致肿瘤细胞恶性增殖和化疗耐药。而且，敲低TLR4后NF-κB抗凋亡通路中XIAP等因子的表达下调，焦亡巨噬细胞对PTCL细胞的恶性促进作用也被逆转。我们的研究结果揭示了焦亡巨噬细胞促进PTCL恶性生物学行为的机制，并阐明了TLR4在此过程中的关键作用。深入分析这一机制将有助于了解肿瘤微环境对PTCL的调节作用，为PTCL的临床治疗提供新思路。

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Pyroptotic macrophages promote proliferation and chemotherapy resistance of peripheral T-cell lymphoma via TLR4 signaling pathway

Peripheral T-cell lymphoma (PTCL) is a highly aggressive type of non-Hodgkin's lymphoma with a poor prognosis. Pyroptosis is a newly discovered procedural cell death mode, which has been implicated to occur in both tumor cells and immune cells. However, the occurrence and effect of pyroptosis on PTCL remain unclear. Here, we found that pyroptosis occurred in interstitial macrophages of PTCL rather than in tumor cells. In clinical specimens, macrophage pyroptosis was associated with a poor prognosis of PTCL. In vitro experiments and gene sequencing results showed that pyroptotic macrophages could upregulate the expression of TLR4 through secreting inflammatory cytokines IL-18. Upregulated TLR4 activated its downstream NF-κB anti-apoptotic signaling pathway, thus leading to malignant proliferation and chemotherapy resistance of tumor cells. Moreover, the expression of factors such as XIAP in the NF-κB anti-apoptotic pathway was downregulated after the knockdown of TLR4, and the malignant promotion effect of pyroptotic macrophages on PTCL cells was also reversed. Our findings revealed the mechanism of pyroptotic macrophages promoting the malignant biological behavior of PTCL and elucidated the key role of TLR4 in this process. In-depth analysis of this mechanism will contribute to understanding the regulatory effect of PTCL by the tumor microenvironment and providing new ideas for the clinical treatment of PTCL.

更新日期：2024-04-13

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