肿瘤细胞治疗研究
英文原题：Pharmacological tumor PDL1 depletion with chlorambucil treats ovarian cancer and melanoma: improves antitumor immunity and renders anti-PDL1-resistant tumors anti-PDL1-sensitive through NK cell effects.
药理学上使用苯丁酸氮芥耗竭肿瘤PDL1，靶向介导治疗耐药的肿瘤内在PDL1信号，尤其是在PDL1耐药肿瘤中，产生PDL1依赖性肿瘤免疫原性，并以免疫依赖性和非依赖性方式抑制肿瘤生长。
背景：肿瘤细胞内程序性死亡配体1（PDL1）可介导病理性信号，调控临床治疗反应；其作用不同于免疫检查点阻断抗体所靶向的细胞表面PDL1。方法：研究者开展肿瘤细胞PDL1耗竭药物筛选，鉴定出FDA批准的苯丁酸氮芥以及9-[2-(膦酰甲氧基)乙基]鸟嘌呤。通过体内外实验评估药理性肿瘤PDL1耗竭的治疗和信号效应，重点研究FDA批准的苯丁酸氮芥单用或联合抗PDL1治疗。结果：表达PDL1的小鼠和人卵巢癌细胞系及小鼠黑色素瘤细胞，体外对苯丁酸氮芥介导的增殖抑制比相应基因性PDL1耗竭细胞更敏感。原位腹膜PDL1表达型ID8agg卵巢癌和皮下B16黑色素瘤肿瘤，体内对苯丁酸氮芥也比相应基因性PDL1耗竭肿瘤更敏感。苯丁酸氮芥增强了原本对PDL1阻断耐药的肿瘤对PDL1疗法的敏感性，并以NK细胞依赖方式增强抗肿瘤免疫和单药及联合治疗效果。体内苯丁酸氮芥介导的PDL1耗竭相对具有肿瘤细胞选择性；在PDL1基因敲除宿主中治疗效果仍然保留，证明治疗效应特异靶向肿瘤PDL1。苯丁酸氮芥诱导PDL1依赖性免疫原性肿瘤细胞死亡，这或可解释免疫贡献。苯丁酸氮芥降低PDL1的机制因肿瘤细胞类型而异，涉及转录或翻译后机制，包括通过GSK3β/β-TRCP通路促进PDL1泛素化。苯丁酸氮芥介导的肿瘤细胞PDL1耗竭还模拟了基因性PDL1耗竭的作用，可降低肿瘤细胞mTORC1活化和肿瘤起始细胞含量，并增强自噬，提示其具有额外治疗潜力。结论：药理性肿瘤PDL1耗竭可借助苯丁酸氮芥靶向介导治疗耐药的肿瘤内在PDL1信号，尤其针对PDL1耐药肿瘤；它可产生PDL1依赖性肿瘤免疫原性，并以免疫依赖及非依赖方式抑制肿瘤生长。该策略可提高部分药物的治疗效果，用于原本难治（包括PDL1阻断难治）的癌症，且可迅速转化至临床。
BACKGROUND: Tumor intracellular programmed cell death ligand-1 (PDL1) mediates pathologic signals that regulate clinical treatment responses distinctly from surface-expressed PDL1 targeted by PDL1 immune checkpoint blockade antibodies. METHODS: We performed a drug screen for tumor cell PDL1 depleting drugs that identified Food and Drug Administration (FDA)-approved chlorambucil and also 9-[2-(phosphonomethoxy)ethyl] guanine. We used in vitro and in vivo assays to evaluate treatment and signaling effects of pharmacological tumor PDL1 depletion focused on chlorambucil as FDA approved, alone or plus PDL1. RESULTS: PDL1-expressing mouse and human ovarian cancer lines and mouse melanoma were more sensitive to chlorambucil-mediated proliferation inhibition in vitro versus corresponding genetically PDL1-depleted lines. Orthotopic peritoneal PDL1-expressing ID8agg ovarian cancer and subcutaneous B16 melanoma tumors were more chlorambucil-sensitive in vivo versus corresponding genetically PDL1-depleted tumors. Chlorambucil enhanced PDL1 efficacy in tumors otherwise PDL1-refractory, and improved antitumor immunity and treatment efficacy in a natural killer cell-dependent manner alone and plus PDL1. Chlorambucil-mediated PDL1 depletion was relatively tumor-cell selective in vivo, and treatment efficacy was preserved in PDL1KO hosts, demonstrating tumor PDL1-specific treatment effects. Chlorambucil induced PDL1-dependent immunogenic tumor cell death which could help explain immune contributions. Chlorambucil-mediated PDL1 reduction mechanisms were tumor cell-type-specific and involved transcriptional or post-translational mechanisms, including promoting PDL1 ubiquitination through the GSK3 / -TRCP pathway. Chlorambucil-mediated tumor cell PDL1 depletion also phenocopied genetic PDL1 depletion in reducing tumor cell mTORC1 activation and tumor initiating cell content, and in augmenting autophagy, suggesting additional treatment potential. CONCLUSIONS: Pharmacological tumor PDL1 depletion with chlorambucil targets tumor-intrinsic PDL1 signaling that mediates treatment resistance, especially in PDL1-resistant tumors, generates PDL1-dependent tumor immunogenicity and inhibits tumor growth in immune-dependent and independent manners. It could improve treatment efficacy of selected agents in otherwise treatment-refractory, including PDL1-refractory cancers, and is rapidly clinically translatable.
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