以色列魏茨曼科学研究所Valery Krizhanovsky和Julia Majewska共同合作，近期取得重要工作进展。他们研究提出，p16依赖性的PD-L1稳定性能够增加调节衰老细胞的免疫监测。相关研究成果2024年8月5日在线发表于《自然—细胞生物学》杂志上。

据介绍，衰老细胞的积累会促进衰老和与年龄相关的疾病，但衰老细胞用来逃避免疫清除并在组织中积累的分子机制仍有待阐明。

研究人员报告了p16阳性衰老细胞上调免疫检查点蛋白程序性死亡配体1（PD-L1），使其在衰老和慢性炎症中积累。p16介导的细胞周期激酶CDK4/6的抑制通过下调其泛素依赖性降解诱导衰老细胞中PD-L1的稳定性。表达p16的衰老肺泡巨噬细胞升高PD-L1以促进免疫抑制环境，从而导致衰老细胞负担的增加。通过激活与效应细胞上Fcγ受体结合的抗PD-L1抗体进行治疗，可以消除PD-L1和p16阳性细胞。

总之，这一研究揭示了p16依赖性调节衰老细胞中PD-L1蛋白稳定性的分子机制，并揭示了靶向PD-L1改善衰老细胞免疫监测和改善衰老相关炎症的潜力。

附：英文原文

Title: p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells

Author: Majewska, Julia, Agrawal, Amit, Mayo, Avi, Roitman, Lior, Chatterjee, Rishita, Sekeresova Kralova, Jarmila, Landsberger, Tomer, Katzenelenbogen, Yonatan, Meir-Salame, Tomer, Hagai, Efrat, Sopher, Ilanit, Perez-Correa, Juan-Felipe, Wagner, Wolfgang, Maimon, Avi, Amit, Ido, Alon, Uri, Krizhanovsky, Valery

Issue&Volume: 2024-08-05

Abstract: The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.

DOI: 10.1038/s41556-024-01465-0

Source: https://www.nature.com/articles/s41556-024-01465-0