Qiao Tianyun, Xiong Yanlu, Feng Yangbo, Guo Wenwen, Zhou Yongsheng, Zhao Jinbo, Jiang Tao, Shi Changhong, Han Yong
Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
School of Basic Medical Sciences, Medical College of Yan'an University, Yanan, China.
Front Oncol. 2021 Mar 30;11:632364. doi: 10.3389/fonc.2021.632364. eCollection 2021.
Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.
免疫疗法是某些癌症的可治愈性治疗方法，但它仍然只对一小部分患者有效，部分原因是肿瘤中缺乏足够的免疫细胞。据报道，靶向乳酸脱氢酶（LDH）以减少乳酸生成可以促进免疫细胞的浸润和活性，并将肿瘤转变为“热肿瘤”。因此，我们构建了一个人源化小鼠模型，以评估单独使用经典LDH抑制剂草氨酸盐和帕博利珠单抗或两者联合用于非小细胞肺癌（NSCLC）的疗效。我们发现，草氨酸盐和帕博利珠单抗单药治疗均显著延缓了肿瘤生长；此外，联合治疗显示出更好的效果。免疫荧光分析表明，草氨酸盐治疗增加了肿瘤中活化CD8 + T细胞的浸润，这可能增强了帕博利珠单抗的治疗效果。用抗CD8抗体治疗人源化小鼠消除了草氨酸盐的治疗效果，表明CD8 + T细胞是介导草氨酸盐作用的主要力量。总之，我们的临床前研究结果表明，草氨酸盐不仅能在高安全剂量下抑制肿瘤生长，还能增强帕博利珠单抗在人外周血单核细胞-人源化肿瘤细胞系（Hu-PBMC-CDX）小鼠中的疗效。我们的研究还为探索其他基于免疫的NSCLC联合疗法的疗效提供了一个临床前模型。
