类抗原呈递并克服小细胞肺癌中的 PD-L1 阻断耐药性

SCI

24 June 2022

Targeting LSD1 rescues MHC class I antigen presentation and overcomes PD-L1 blockade resistance in small cell lung cancer

（J Thorac Oncol；IF：15.609）

• Nguyen EM, Taniguchi H, Chan JM et al. Targeting LSD1 rescues MHC class I antigen presentation and overcomes PD-L1 blockade resistance in small cell lung cancer. J Thorac Oncol 2022. DOI: 10.1016/j.jtho.2022.05.014

• Corresponding author:Charles M Rudin，rudinc@mskcc.org，1275 York Avenue, New York, NY 10065 (United States)，Phone: (646) 888-4527

Introduction 介绍

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that is characterized by early acquired therapeutic resistance and modest benefit from immune checkpoint blockade (ICB). Repression of the major histocompatibility complex class I (MHC-I) represents a key mechanism driving resistance to T cell-based immunotherapies.

小细胞肺癌(SCLC)是一种高度侵袭性的神经内分泌肿瘤，其特点是早期获得性治疗耐药性和免疫检查点封锁(ICB)的适度受益。主要组织相容性复合体I类(MHC-I)的抑制是导致T细胞免疫治疗耐药性的关键机制。

  Methods 方法

We evaluated the role of the lysine-specific demethylase 1 (LSD1) as a determinant of MHC-I expression, functional antigen presentation, and immune activation in SCLC in vitro and in vivo, through evaluation of both human SCLC cell lines and immunocompetent mouse models. 

通过对人SCLC细胞系和免疫小鼠模型的评价，我们评估了赖氨酸特异性去甲基化酶1 (LSD1)在体外和体内的作用，它是MHC-I表达、功能性抗原呈递和SCLC免疫激活的决定因素。

Results 结果

We demonstrate that targeted inhibition of LSD1 in SCLC restores MHC-I cell surface expression and transcriptionally activates genes encoding the antigen presentation pathway. LSD1 inhibition further activates interferon signaling, induces tumor intrinsic immunogenicity, and sensitizes SCLC cells to MHC-I-restricted T cell cytolysis. Combination of LSD1 inhibitor with ICB augments the anti-tumor immune response in refractory SCLC models. Together, these data define a role for LSD1 as a potent regulator of MHC-I antigen presentation and provide rationale for combinatory use of LSD1 inhibitors with ICB to improve therapeutic response in SCLC.

我们证明，靶向抑制LSD1在SCLC中可以恢复MHC-I细胞表面表达，并转录激活编码抗原递呈途径的基因。LSD1抑制进一步激活干扰素信号，诱导肿瘤固有免疫原性，并使SCLC细胞对MHC-I限制性T细胞的细胞溶解敏感。在难治性SCLC模型中，LSD1抑制剂与ICB联合可增强抗肿瘤免疫反应。总之，这些数据确定了LSD1作为MHC-I抗原呈递的有效调控因子的作用，并为联合使用LSD1抑制剂和ICB来改善SCLC的治疗反应提供了理论依据。

Conclusions 结论

Epigenetic silencing of MHC-I in SCLC contributes to its poor response to ICB. Our study identifies a previously uncharacterized role for LSD1 as a regulator of MHC-I antigen presentation in SCLC. LSD1 inhibition enables MHC-I-restricted T cell cytolysis, induces immune activation, and augments the anti-tumor immune response to ICB in SCLC.

SCLC中MHC-I的表观遗传沉默导致其对ICB反应较差。我们的研究确定了LSD1在SCLC中作为MHC-I抗原呈递调节因子的一个以前未被描述的作用。LSD1抑制使MHC-I限制性T细胞溶解，诱导免疫激活，并增强SCLC对ICB的抗肿瘤免疫应答。