Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina.
Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
Cancer Res Commun. 2024 Oct 1;4(10):2673-2684. doi: 10.1158/2767-9764.CRC-24-0264.
The molecular mechanisms regulating CD8+ cytotoxic T lymphocytes (CTL) are not fully understood. Here, we show that the peroxisome proliferator-activated receptor δ (PPARδ) suppresses CTL cytotoxicity by inhibiting RelA DNA binding. Treatment of ApcMin/+ mice with the PPARδ agonist GW501516 reduced the activation of normal and tumor-associated intestinal CD8+ T cells and increased intestinal adenoma burden. PPARδ knockout or knockdown in CTLs increased their cytotoxicity against colorectal cancer cells, whereas overexpression of PPARδ or agonist treatment decreased it. Correspondingly, perforin, granzyme B, and IFNγ protein and mRNA levels were higher in PPARδ knockout or knockdown CTLs and lower in PPARδ overexpressing or agonist-treated CTLs. Mechanistically, we found that PPARδ binds to RelA, interfering with RelA-p50 heterodimer formation in the nucleus, thereby inhibiting its DNA binding in CTLs. Thus, PPARδ is a critical regulator of CTL effector function. Significance: Here, we provide the first direct evidence that PPARδ plays a critical role in suppressing the immune response against tumors by downregulating RelA DNA-binding activity. This results in decreased expression of perforin, granzyme B, and IFNγ. Thus, PPARδ may serve as a valuable target for developing future cancer immunotherapies.
调控 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 的分子机制尚不完全清楚。在这里，我们表明过氧化物酶体增殖物激活受体 δ (PPARδ) 通过抑制 RelA DNA 结合来抑制 CTL 细胞毒性。用 PPARδ 激动剂 GW501516 处理 ApcMin/+ 小鼠可减少正常和肿瘤相关的肠道 CD8+T 细胞的激活，并增加肠道腺瘤负担。CTL 中 PPARδ 的敲除或敲低增加了其对结直肠癌细胞的细胞毒性，而 PPARδ 的过表达或激动剂处理则降低了其细胞毒性。相应地，穿孔素、颗粒酶 B 和 IFNγ 蛋白和 mRNA 水平在 PPARδ 敲除或敲低 CTL 中较高，而在 PPARδ 过表达或激动剂处理 CTL 中较低。从机制上讲，我们发现 PPARδ 与 RelA 结合，干扰核内 RelA-p50 异二聚体的形成，从而抑制其在 CTL 中的 DNA 结合。因此，PPARδ 是 CTL 效应功能的关键调节因子。意义：在这里，我们提供了第一个直接证据，表明 PPARδ 通过下调 RelA DNA 结合活性在抑制针对肿瘤的免疫反应中起关键作用。这导致穿孔素、颗粒酶 B 和 IFNγ 的表达减少。因此，PPARδ 可能成为开发未来癌症免疫疗法的有价值的靶点。
