MEDICINE AND HEALTH

New research proposes anti-tumor angiogenesis treatment strategies


The team of Academician Fan Xianqun of the Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine found that the proportion of programmed death ligand 1 (PD-L1) in the nucleus of uveal melanoma (UM) was increased, and the expression of early growth response factor 1 (EGR1) was activated by transcription, which could promote tumor angiogenesis. Anti-PD-L1 immunotherapy combined with histone deacetylase 2 (HDAC2) inhibitors can weaken UM tumor angiogenesis, so the researchers propose a new anti-tumor angiogenesis treatment strategy. On March 28, the study was published in Molecular Research.

Schematic diagram of nucleus PD-L1 promoting UM vascularization. Photo courtesy of the research team

Immunotherapy is the third revolution in the history of tumor treatment after chemotherapy, radiotherapy and targeted therapy. Among them, PD-L1 is one of the most critical tumor immunosuppressive molecules. PD-L1 on the surface of tumor cell membrane inhibits the proliferation and activation of T cells by interacting with programmed death receptor 1 (PD-1) on the T cell membrane in the microenvironment, thereby mediating the immune escape of tumor cells, and rapid growth and metastasis of tumor cells out of control. In the past decade, anti-PD-1/PD-L1 immunotherapy has achieved obvious results in tumor treatment. However, the anti-PD-L1 efficacy in UM is not good.

The study found that lysine at position 263 of PD-L1 on breast cancer cell membranes can undergo acetylation modification. PD-L1 deacetylated by HDAC2 can enter the nucleus through the nuclear pore and transcribe and activate gene expression that evades immune surveillance-related pathways, thereby affecting the efficacy of PD-L1 blocking therapy. This suggests that nuclear PD-L1 has important cancer-promoting functions and may be an important reason for the tolerance of anti-PD-L1 immunotherapy. However, the distribution characteristics and functions of PD-L1 in UM are unclear.

Relying on clinical sample resources, the researchers found that the expression level of nuclear PD-L1 in UM was elevated and correlated with poor prognosis. Further studies found that nuclear PD-L1 had no significant effect on the proliferation and migration ability of UM cells, but could significantly promote the provascularization ability of cells.

Through joint analysis, the researchers found that nuclear PD-L1 can transcribe and activate the expression of the provascularization factor EGR1. Therefore, anti-PD-L1 immunotherapy combined with HDAC2 can inhibit the reduction of tumor angiogenesis in UM, which provides a new strategy for antitumor therapy. (Source: China Science News, Zhang Shuanghu, Huang Xin)

Related paper information:https://doi.org/10.1038/s41421-023-00521-7



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