New Insights into How Immune Cells Can Undermine Cancer Treatments

Recent research from Memorial Sloan Kettering Cancer Center has unveiled a crucial mechanism by which engineered immune cells, such as CAR-T and CAR-NK therapies, may fail during cancer treatment. These modified cells, designed to target and destroy tumors, sometimes self-destruct before accomplishing their goal. The investigation focused on a protein called FAS, found on immune cell surfaces, and its interaction with FAS ligand (FAS-L). Previously, it was understood that immune cells lose effectiveness due to interactions between FAS and FAS-L, which activate a process called apoptosis, leading to cell death.

What’s groundbreaking in this discovery is the finding that immune cells themselves produce FAS-L, contributing to their own self-destruction. Dr. Klebanoff explains that these engineered cells carry high levels of FAS-L, which acts like a sword, enabling them to commit suicide or kill each other. This self-inflicted damage reduces their longevity and impairs the effectiveness of cell-based therapies.

To combat this, researchers engineered a decoy receptor called FAS-DNR that binds to FAS-L without triggering cell death. Incorporating this decoy into CAR-T and CAR-NK cells significantly extended their lifespan and enhanced tumor-fighting capabilities. Analyzing cells from over 50 cancer patients, the team confirmed that immune cells were the primary source of FAS-L, even after genetic engineering, and that FAS-L production was responsible for self-elimination in therapy.

These insights open new avenues for improving cellular immunotherapies. By blocking the FAS-L and FAS interaction, it’s possible to boost the persistence and potency of these treatments. The approach is already being tested in clinical trials. Overall, the discovery underscores the importance of understanding immune cell self-regulation to refine and improve therapies against cancer.

This research, published in Nature Cancer, highlights the potential for genetically reengineering immune cells to resist self-destruction, ultimately leading to more durable and effective cancer treatments.