Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T cell killing. Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T cell killing

The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically “cold” tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with A) decreased neuroendocrine characteristics and B) activation of NOTCH signaling. We previously showed that inhibition of the LSD1 demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD1 inhibition in SCLC. Overall design: Identification of differentially expressed genes regulated by exposure to the LSD1 inhibitor bomedemstat (BOM) in cultured murine SCLC cells and an immunocompetent murine flank tumor model of SCLC. Cultured cells were treated with BOM for 96h, or with BOM or control for 10d with or without IFNg for the last 48h. Flank tumors were exposed to BOM or vehicle, with or without anti-PD1 immune checkpoint inhibitor (ICI) antibody, for 16-17 days.

将免疫检查点阻断（immune checkpoint blockade, ICB）联合铂类/依托泊苷化疗方案，已改变了小细胞肺癌（small cell lung cancer, SCLC）的临床治疗标准。然而，仅在治疗中加入ICB仅能小幅改善临床结局，这可能反映出尽管SCLC的突变负荷较高，但其免疫“冷”肿瘤微环境的占比极高。尽管如此，仍有部分患者能从ICB治疗中明确获益；近期研究表明，SCLC患者对ICB的临床应答与以下两点相关：A）神经内分泌特征减弱，B）NOTCH信号通路（NOTCH signaling）激活。我们此前的研究证实，抑制LSD1去甲基化酶（LSD1 demethylase）可激活NOTCH信号通路，并抑制SCLC的神经内分泌表型，这促使我们探究抑制LSD1是否能够增强SCLC对PD-1抑制（PD1 inhibition）的应答。

总体实验设计：
本研究旨在鉴定经LSD1抑制剂bomedemstat（BOM）处理后，培养的小鼠SCLC细胞以及免疫健全的小鼠SCLC皮下移植瘤模型中受调控的差异表达基因。对培养细胞分别进行如下处理：以BOM处理96小时；或以BOM或对照溶剂处理10天，并在最后48小时加入或不加入干扰素γ（IFNg）。对皮下移植瘤分别进行如下处理：以BOM或溶剂对照处理，联合或不联合抗PD-1免疫检查点抑制剂（immune checkpoint inhibitor, ICI）抗体，处理时长为16至17天。