Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, P. R. China.
Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, P. R. China.
Sci Adv. 2024 Jun 7;10(23):eadl6083. doi: 10.1126/sciadv.adl6083. Epub 2024 Jun 5.
Hepatocellular carcinoma (HCC) acquires an immunosuppressive microenvironment, leading to unbeneficial therapeutic outcomes. Hyaluronan-mediated motility receptor (HMMR) plays a crucial role in tumor progression. Here, we found that aberrant expression of HMMR could be a predictive biomarker for the immune suppressive microenvironment of HCC, but the mechanism remains unclear. We established an HMMR liver cancer mouse model to elucidate the HMMR-mediated mechanism of the dysregulated "don't eat me" signal. HMMR knockout inhibited liver cancer growth and induced phagocytosis. HMMR liver cancer cells escaped from phagocytosis via sustaining CD47 signaling. Patients with HMMRCD47 expression showed a worse prognosis than those with HMMRCD47 expression. HMMR formed a complex with FAK/SRC in the cytoplasm to activate NF-κB signaling, which could be independent of membrane interaction with CD44. Notably, targeting HMMR could enhance anti-PD-1 treatment efficiency by recruiting CD8 T cells. Overall, our data revealed a regulatory mechanism of the "don't eat me" signal and knockdown of HMMR for enhancing anti-PD-1 treatment.
肝细胞癌 (HCC) 获得免疫抑制微环境，导致治疗效果不佳。透明质酸介导的运动受体 (HMMR) 在肿瘤进展中起着至关重要的作用。在这里，我们发现 HMMR 的异常表达可能是 HCC 免疫抑制微环境的预测性生物标志物，但机制尚不清楚。我们建立了 HMMR 肝癌小鼠模型，以阐明失调的“别吃我”信号的 HMMR 介导机制。HMMR 敲除抑制肝癌生长并诱导吞噬作用。HMMR 肝癌细胞通过维持 CD47 信号逃避吞噬作用。与 HMMRCD47 表达的患者相比，HMMRCD47 表达的患者预后更差。HMMR 在细胞质中与 FAK/SRC 形成复合物以激活 NF-κB 信号，该信号可能独立于与 CD44 的膜相互作用。值得注意的是，靶向 HMMR 可以通过招募 CD8 T 细胞来增强抗 PD-1 治疗的效果。总体而言，我们的数据揭示了“别吃我”信号的调节机制以及敲低 HMMR 增强抗 PD-1 治疗的机制。
