Nat Cancer: Lui Zhimin/Hatchie jointly reveals a new mechanism to overcome immune checkpoint inhibitor resistance

Patients with non-small cell lung carcinoma (NSCLC) activated by EGFR mutation are not sensitive to immune checkpoint inhibitor therapy, which is the bottleneck
of lung cancer immunotherapy.
The continuous discovery and elucidating of new mechanisms of tumor immune evasion regulated by tumor microenvironment have brought new hope
to these NSCLC patients.

On October 21, 2022, the Lui Zhimin team of the Institute of Translational Medicine of Zhejiang University/The First Affiliated Hospital of Zhejiang University School of Medicine and the team of the National Cancer Center/Cancer Hospital of the Chinese Academy of Medical Sciences published an online article entitled "Silencing EGFR-upregulated expression of CD55 and CD59 activates the" in the form of a cover article in Nature Cancer complement system and sensitizes lung cancer to checkpoint blockade", revealing that NSCLC patients with an EGFR mutation who can overcome EGFR mutations with CD55/CD59 antibodies and PD-1 antibodies do not respond to
immune checkpoint inhibitor therapy.

This achievement is also an important collaboration between
the Lui Zhimin/Hejie team of the National Basic Science Center project "Mesoscale Research on Tumor Material and Energy Dynamics".

The complement system recognizes foreign pathogens and autocells expressing abnormal surface molecules to trigger the release of inflammatory mediators, recruitment of immune cells, phagocytosis, and cell lysis
.
At the same time, the complement system is tightly negatively regulated and inhibited
by membrane-bound complement regulatory proteins (mCRPs, including CD55 and CD59).

Lui and Hatchie's team found that EGFR mutation activation in NSCLC cells increased the expression of CD55 and CD59 in tumor cells, inhibited complement activation and CD8+ T cell activity
.
Further studies found that EGFR mutation activation caused β-catenin to bind to the LINC00973 promoter, thereby inducing LINC00973 expression
.
LINC00973 upregulates the expression of CD55 and CD59 by adsorbing miR-216b and miRNA-150, thereby inhibiting the function of immune cells in the tumor microenvironment mediated by complement activation, and finally achieving tumor immune escape
.
Studies have shown that the combination of CD55/CD59 antibody and PD-1 antibody is more effective in promoting the infiltration of CD8+ T cells and M1 macrophages in tumors, thereby inhibiting tumor growth and significantly prolonging the survival time
of tumor-bearing mice.

This study revealed the intrinsic regulatory relationship between complement and immune cells in the tumor microenvironment (Figure 1), providing preclinical evidence that the new strategy of combined blocking mCRP function and PD-1/PD-L1 checkpoint therapy for EGFR mutation activation of NSCLC has high clinical translational value
.

A schematic diagram of the molecular mechanism revealed in this study is as follows:

This study is another important achievement
of Lui Zhimin's team in the research direction of tumor metabolic immunity, following the mechanism of tumor cell AKT/β-catenin pathway regulation of immune checkpoint PD-L1 (Journal of Experimental Medicine, August 2020) and the disclosure of tumor cell Warburg effect to promote tumor immune evasion (Cell Metabolism, August 2022).

Original source:

Shao F, Gao Y, Wang W, He H, Xiao L, Geng X, Xia Y, Guo D, Fang J, He J, Lu Z.
Silencing EGFR-upregulated expression of CD55 and CD59 activates the complement system and sensitizes lung cancer to checkpoint blockade.
Nat Cancer (Report missing IFs).
2022 Oct; 3(10):1192-1210.
doi: 10.
1038/s43018-022-00444-4.