Nature: Chinese scientists discover new targets for tumor immunotherapy

On September 6, Fudan University and the Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences cooperated to publish a paper online in the journal Nature and discovered a new, highly conserved tumor immunosuppressive receptor CD300ld.

Research diagram Photo courtesy of interviewee

In recent years, immune checkpoint blockade (ICB) therapy represented by molecules such as PD-1/PD-L1/CTLA-4 has made rapid progress in the field of tumor treatment. However, the effect of existing ICBs varies greatly among patients with different tumors, and a considerable proportion of patients do not respond and the proportion of long-term benefit is lower. The tumor immune microenvironment contains a large population of immune-suppressing myeloid cells, which plays a key role in tumor development and treatment tolerance, and is a serious hindrance to existing immunotherapy.

Pathologically activated neutrophils (also known as polymorphonuclear myeloid-derived suppressor cells, PMN-MDSCs) are important components of the immunosuppressive microenvironment. Numerous clinical evidence suggests that neutrophils are deeply involved in tumor progression and are significantly associated with patient outcomes. Therefore, it is of great clinical significance to explore the role of neutrophils in tumor progression and find specific targets for this group of cells.

“Unlike normal neutrophils, PMN-MDSCs have a strong inhibitory effect on lymphocyte killing, participating in tumor progression through multiple pathways. Finding specific targets for PMN-MDSCs to regulate the tumor immune microenvironment is the focus and challenge of current immunotherapy. Luo Min, a co-corresponding author of the paper and a young researcher at Fudan University, told China Science News.

Using CRISPR-Cas9 in vivo screening and serial tumor model verification, the researchers found that CD300ld, a key functional receptor of PMN-MDSCs, plays a key role in tumor immune regulation. CD300ld simultaneously regulates the recruitment of PMN-MDSCs and their immunosuppressive function through the STAT3-S100A8/A9 axis, promoting the establishment of immunosuppressive microenvironment and tumor progression.

Further studies have shown that blocking CD300ld can significantly reduce the recruitment of PMN-MDSCs and their immunosuppressive activity, and reshape the tumor immune microenvironment from an inhibitory state to an activated state, thereby producing a broad-spectrum anti-tumor effect.

“The CD300ld target shows good safety, conservatism, anti-tumor efficacy, and synergy with PD1 target, and is expected to become a new ideal target for tumor immunotherapy.” Luo Min said.

Chaoxiong Wang, postdoctoral fellow at the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Zheng Xichen, postdoctoral fellow at the Institute of Biomedical Sciences, Fudan University, and Jinlan Zhang, research assistant, are co-first authors of this paper. Luo Min, a young researcher at the Institute of Biomedical Sciences, Fudan University, Lu Zhigang and Gao Hai, and Zhao Yun, a researcher at the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, are co-corresponding authors of this paper. (Source: Liu Runan, China Science News)

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