Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-004129.
LTX-315 is an oncolytic peptide deriving from bovine lactoferrin, with the ability to induce cancer immunogenic cell death. However, the mechanism used by LTX-315 to trigger the antitumor immune response is still poorly understood. The expression of programmed cell death ligand 1 (PD-L1) largely determines the efficacy and effectiveness of cancer immunotherapies targeting this specific immune checkpoint. This study aimed to demonstrate the potential effect and mechanism of LTX-315 in PD-L1 inhibition-induced anti-pancreatic cancer immunity.
Both immunodeficient and immunocompetent mouse models were used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Flow cytometry and immunohistochemistry were used to assess the immune microenvironment. Multiomic analysis was used to identify the potential target and down-streaming signaling pathway. Both in-house tissue microarray and open accessed The Cancer Genome Atlas data sets were used to evaluate the clinical relevance in pancreatic cancer prognosis.
LTX-315 treatment inhibited PD-L1 expression and enhanced lymphocyte infiltration in pancreatic tumors. ATP11B was identified as a potential target of LTX-315 and a critical regulator in maintaining PD-L1 expression in pancreatic cancer cells. As regards the mechanism, ATP11B interacted with PD-L1 in a CKLF-like MARVEL transmembrane domain containing 6 (CMTM6)-dependent manner. The depletion of ATP11B promoted CMTM6-mediated lysosomal degradation of PD-L1, thus reactivating the immune microenvironment and inducing an antitumor immune response. The significant correlation among ATP11B, CMTM6, and PD-L1 was confirmed in clinical samples of pancreatic cancer.
LTX-315 was first identified as a peptide drug inducing PD-L1 downregulation via ATP11B. Therefore, LTX-315, or the development of ATP11B-targeting drugs, might improve the efficacy of cancer immunotherapy.
LTX-315 是一种源自牛乳铁蛋白的溶瘤肽，具有诱导癌症免疫原性细胞死亡的能力。然而，LTX-315 触发抗肿瘤免疫反应的机制仍知之甚少。程序性细胞死亡配体 1（PD-L1）的表达在很大程度上决定了针对这一特定免疫检查点的癌症免疫疗法的疗效和有效性。本研究旨在证明 LTX-315 抑制 PD-L1 诱导抗胰腺癌免疫的潜在作用和机制。
使用免疫缺陷和免疫功能正常的小鼠模型评估单药和联合治疗的疗效。流式细胞术和免疫组织化学用于评估免疫微环境。多组学分析用于鉴定潜在的靶标和下游信号通路。使用内部组织微阵列和公开获取的癌症基因组图谱数据集评估在胰腺癌预后中的临床相关性。
LTX-315 治疗抑制了胰腺肿瘤中 PD-L1 的表达并增强了淋巴细胞浸润。ATP11B 被鉴定为 LTX-315 的潜在靶标，也是维持胰腺癌细胞中 PD-L1 表达的关键调节因子。就机制而言，ATP11B 在 CKLF 样 MARVEL 跨膜域包含 6（CMTM6）依赖性方式与 PD-L1 相互作用。ATP11B 的耗竭促进了 CMTM6 介导的 PD-L1 溶酶体降解，从而重新激活免疫微环境并诱导抗肿瘤免疫反应。在胰腺癌的临床样本中证实了 ATP11B、CMTM6 和 PD-L1 之间的显著相关性。
LTX-315 首次被鉴定为一种通过 ATP11B 诱导 PD-L1 下调的肽类药物。因此，LTX-315 或开发针对 ATP11B 的药物可能会提高癌症免疫疗法的疗效。
