Science cover: ESCRT, a potential new target for cancer immunotherapy

Normal cells tend to have a common feature, a protective membrane structure formed by a double layer of phospholipids, also known as the cytoplasmic membrane

Based on this characteristic of cancer cells, cytotoxic T lymphocytes (CTLs) secrete two proteins specifically to disrupt the plasma membrane and promote cancer cell death

However, cancer cells are good at evading the lethal attack of cytotoxic T lymphocytes (CTL), and one of the methods is to effectively repair the damage of their own cell membranes, but the specific mechanism is not clear

On April 22, 2022, researchers from Genentech published a research paper titled: ESCRT-mediated membrane repair protects tumor-derived cells against T cell attack in the journal Science, and appeared on the cover of the journal, sparking people's attention.

This study found and confirmed that ESCRT (endosome sorting and transport complex)-mediated cell membrane repair mechanism leads cancer cells to evade lethal attack by cytotoxic T lymphocytes (CTL), and inhibition of ESCRT pathway can promote the killing of CTL on cancer cells , which presents a new potential therapeutic target for tumor immunotherapy

The endosomal sorting complex required for transport (ESCRT) system is a molecular machine in eukaryotic cells that completes endosome membrane invagination to form multi-vesicular bodies (MVBs).

With the help of high-resolution imaging and functional analysis of live cells, a research team from Genetech, a US-based genetic engineering technology company, found that the endosomal protein sorting transporter (ESCRT) produced by cancer cells can be used to defend against CTL.

Therefore, the research team used two alternative methods: one used CRISPR gene editing to knock out the Chmp4b gene in the ESCRT pathway, and the other was a mutant that overexpressed the phosphorylase VPS4 in the ESCRT pathway

A killer T cell (red) engages and destroys a giant ovarian cancer cell (green) as shown in the moving image.

For the results of this study, Dr.

Dr.

"This study shows that cancer cells use a common membrane repair mechanism to protect themselves from immune system attack, which is both unexpected and expected," said the study's corresponding author, Dr.

Collectively, this study reveals that ESCRT-mediated membrane repair is an important and previously unappreciated way by which cancer cells evade killing by the immune system

Dr.

Original source:

Ritter AT, Shtengel G, Xu CS, Weigel A, Hoffman DP, Freeman M, Iyer N, Alicodej N, Ackerman D, Voskoboinik I, Trapani J, Hess HF, Mellman I.
ESCRT-mediated membrane repair protects tumor-derived cells against T cell attack.
Science.
2022 Apr 22;376(6591):377-382.