Scholarlink

<p>Immune checkpoint inhibitors (ICIs), especially anti-PD-1 immunotherapy, offer a new treatment option for tumor patients. However, its efficacy is limited in the most of patients with immunologically “cold” tumors. An important histone demethylase, histone lysine-specific demethylase 1 (LSD1/KDM1A), plays a significant role in T cell regulation. Combining LSD1 inhibitors with anti-PD-1 mAb has shown improved anti-tumor effects in various solid tumors. Specifically, in gastric cancer (GC), LSD1 knockdown boosts T cell-mediated anti-tumor immunity. Nevertheless, currently, this effect is only related to PD-L1 in exosomes. Therefore, further research on the molecular mechanisms of LSD1 in regulating T cells in GC is needed. Using TIMER 2.0 and GEPIA 2 databases, we analyzed LSD1 expression in GC and its gene correlations. Lentiviral transfection was utilized to construct a control cell line (shControl) and an LSD1 knockdown cell line (shLSD1). The mRNA and protein levels of LSD1 and immune-related cytokines were measured through real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. We examined the role of LSD1 knockdown in regulating T cell anti-tumor immunity via transcriptome sequencing (RNA-seq). Mouse subcutaneous graft tumor models and in vitro conditioned culture models were established, and the altered functional phenotypes of T cells in mice and in vitro were assessed by RT-qPCR and flow cytometry. Genetic inhibition of LSD1 in GC cells increased T cell proliferation, CD8<sup>+</sup> activation, and chemotaxis in vitro. Pharmacological inhibition of LSD1 curbed tumor growth in vivo. Remarkably, the combination LSD1 inhibitors with PD-1/PD-L1 blockers led to greater efficacy. At the molecular level, LSD1 knockdown induced the transcription of tumor necrosis factor ligand superfamily member 14 (TNFSF14). As a result, T cell-mediated anti-tumor immunity was improved. Inhibiting LSD1 in GC upregulates TNFSF14 expression, which in turn promotes T cell proliferation, CD8<sup>+</sup> activation, and chemotaxis. This enhancement of T cell-mediated anti-tumor immunity is further amplified when LSD1 inhibitors are used alongside PD-(L)1 blockers, facilitating the activation of CD8<sup>+</sup> T cells in the spleen and improving leukocyte infiltration in the tumor.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Inhibition of LSD1 enhances T cells anti-tumor immunity by promoting TNFSF14 expression in gastric cancer

  • 期刊论文

  • 发表日期：

    2025年10月15日

查看全文
  • Xueqing Xie,
  • Wei Lu,
  • Qingling Yin,
  • Meijun Hou,
  • Jingjing Tian,
  • Xunsheng Chen,
  • Yuanling Zhang,
  • Lili Zeng,
  • Jie Ding

摘要

Immune checkpoint inhibitors (ICIs), especially anti-PD-1 immunotherapy, offer a new treatment option for tumor patients. However, its efficacy is limited in the most of patients with immunologically “cold” tumors. An important histone demethylase, histone lysine-specific demethylase 1 (LSD1/KDM1A), plays a significant role in T cell regulation. Combining LSD1 inhibitors with anti-PD-1 mAb has shown improved anti-tumor effects in various solid tumors. Specifically, in gastric cancer (GC), LSD1 knockdown boosts T cell-mediated anti-tumor immunity. Nevertheless, currently, this effect is only related to PD-L1 in exosomes. Therefore, further research on the molecular mechanisms of LSD1 in regulating T cells in GC is needed. Using TIMER 2.0 and GEPIA 2 databases, we analyzed LSD1 expression in GC and its gene correlations. Lentiviral transfection was utilized to construct a control cell line (shControl) and an LSD1 knockdown cell line (shLSD1). The mRNA and protein levels of LSD1 and immune-related cytokines were measured through real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. We examined the role of LSD1 knockdown in regulating T cell anti-tumor immunity via transcriptome sequencing (RNA-seq). Mouse subcutaneous graft tumor models and in vitro conditioned culture models were established, and the altered functional phenotypes of T cells in mice and in vitro were assessed by RT-qPCR and flow cytometry. Genetic inhibition of LSD1 in GC cells increased T cell proliferation, CD8+ activation, and chemotaxis in vitro. Pharmacological inhibition of LSD1 curbed tumor growth in vivo. Remarkably, the combination LSD1 inhibitors with PD-1/PD-L1 blockers led to greater efficacy. At the molecular level, LSD1 knockdown induced the transcription of tumor necrosis factor ligand superfamily member 14 (TNFSF14). As a result, T cell-mediated anti-tumor immunity was improved. Inhibiting LSD1 in GC upregulates TNFSF14 expression, which in turn promotes T cell proliferation, CD8+ activation, and chemotaxis. This enhancement of T cell-mediated anti-tumor immunity is further amplified when LSD1 inhibitors are used alongside PD-(L)1 blockers, facilitating the activation of CD8+ T cells in the spleen and improving leukocyte infiltration in the tumor.