Genentech Team Discovers New Cancer Immunotherapy Target - ESCRT

We know that cytotoxic T lymphocytes (CTL) and natural killer (NK) cells can kill virus-infected cells and tumor cells by releasing perforin and granzymes. Perforin causes damage on the plasma membrane of target cells, and granzymes enter the cell through the damaged hole and induce apoptosis.

Cancer cells, however, are adept at using a variety of strategies to evade the immune system. A research team led by Roche's Genentech company has identified a way that cancer cells resist T-cell attack by repairing membrane damage.

Briefly, they found that cancer cells can recruit endosomal sorting transport complex (ESCRT) proteins to clear cell membrane damage, thereby preventing the entry of granzymes. The results were published on April 21 as a Science cover paper.

Previous studies have shown that ESCRT proteins can repair plasma membrane holes caused by bacterial pore-forming toxins, mechanical damage, and laser ablation. The protein is transiently recruited to sites of membrane damage in a Ca2+-dependent manner, where they assemble budding structures and shed to eliminate damage and restore plasma membrane integrity.

In the study, using live-cell imaging, the researchers found that cancer cells recruited the ESCRT protein to match when and where T cells caused damage. After being attacked by killer T cells, ESCRT proteins precisely accumulate at the cytolytic synapse, the site where T cells bind to target cells and initiate the killing process.

To further verify this finding, the researchers inhibited ESCRT by knocking out the gene encoding the ESCRT protein (Chmp4b) through CRISPR technology, or upregulating the expression of a gene fragment {VPS4a E228Q (E228Q,Glu228 → Gln)} that impairs ESCRT function. ESCRT-inhibited cancer cells were more efficiently killed by T cells than control cells.

In conclusion, this study demonstrates that ESCRT-mediated active membrane repair of perforin pore may limit the accessibility of granzymes to target cells, allowing cancer cells to survive cytotoxic challenge. These findings provide new insights into how tumor cells evade targeting by the immune system and may help improve the efficacy of cancer immunotherapies such as PD-1/L1 checkpoint inhibitors and CAR-T cell therapy.

Ira Mellman, Ph.D., vice president of cancer immunology at Genentech, noted that while inhibiting ESCRT is a promising strategy for enhancing T-cell attack on tumor cells, it is unclear how this can be achieved with drugs, since ESCRT proteins also have an impact on cell division. critical. However, he suspects that some members of the family may be needed only for membrane repair and have no effect on other functions. This may offer a way out.

Dr. Norma Andrews, a cell biologist at the University of Maryland, believes that future research will also explore the role of other cellular processes in repairing membrane damage.