Division of Dermatology, Department of Surgery, City of Hope, Duarte, California, USA; Beckman Research Institute, City of Hope, Duarte, California, USA.
Beckman Research Institute, City of Hope, Duarte, California, USA; Integrative Genomics and Bioinformatics, City of Hope, Duarte, California, USA; Computational and Quantitative Medicine, City of Hope, Duarte, California, USA.
J Invest Dermatol. 2023 Aug;143(8):1569-1578.e5. doi: 10.1016/j.jid.2023.02.017. Epub 2023 Mar 1.
Cutaneous T-cell lymphoma (CTCL) is an incurable and cosmetically disfiguring disease associated with microenvironmental signals. We investigated the effects of CD47 and PD-L1 immune checkpoint blockades, as a strategy for targeting both innate and adaptive immunity. CIBERSORT analysis identified the immune-cell composition in the CTCL tumor microenvironment and the immune checkpoint expression profile for each immune-cell gene cluster from CTCL lesions. We investigated the relationship between MYC and CD47 and PD-L1 expression and found that MYC short hairpin RNA knockdown and MYC functional suppression by TTI-621 (SIRPαFc) and anti-PD-L1 (durvalumab) in CTCL cell lines reduced the expression of CD47 and PDL1 mRNA and protein as measured by qPCR and flow cytometry, respectively. In vitro, blockade of the CD47-SIRPα interaction with TTI-621 increased the phagocytic activity of macrophages against CTCL cells and enhanced CD8 T-cell-mediated killing in a mixed leucocyte reaction. Moreover, TTI-621 synergized with anti-PD-L1 in macrophages reprogram to M1-like phenotypes and inhibited CTCL cell growth. These effects were mediated by cell death-related pathways, including apoptosis, autophagy, and necroptosis. Collectively, our findings show that CD47 and PD-L1 are critical regulators of immune surveillance in CTCL and that dual targeting of CD47 and PD-L1 will provide insight into tumor immunotherapy for CTCL.
皮肤 T 细胞淋巴瘤（CTCL）是一种无法治愈且影响容貌的疾病，与微环境信号有关。我们研究了 CD47 和 PD-L1 免疫检查点阻断的效果，作为靶向固有和适应性免疫的策略。CIBERSORT 分析确定了 CTCL 肿瘤微环境中的免疫细胞组成，以及来自 CTCL 病变的每个免疫细胞基因簇的免疫检查点表达谱。我们研究了 MYC 和 CD47 与 PD-L1 表达之间的关系，发现 MYC 短发夹 RNA 敲低和 MYC 通过 TTI-621（SIRPαFc）和抗 PD-L1（durvalumab）的功能抑制，分别降低了 CTCL 细胞系中 CD47 和 PDL1 mRNA 和蛋白的表达，这是通过 qPCR 和流式细胞术测量的。在体外，用 TTI-621 阻断 CD47-SIRPα 相互作用增加了巨噬细胞对 CTCL 细胞的吞噬活性，并增强了混合白细胞反应中 CD8 T 细胞介导的杀伤作用。此外，TTI-621 与巨噬细胞重编程为 M1 样表型的抗 PD-L1 协同作用，并抑制 CTCL 细胞生长。这些作用是通过细胞死亡相关途径介导的，包括细胞凋亡、自噬和坏死性凋亡。总之，我们的研究结果表明，CD47 和 PD-L1 是 CTCL 中免疫监视的关键调节因子，双重靶向 CD47 和 PD-L1 将为 CTCL 的肿瘤免疫治疗提供新的见解。
