Researchers from Columbia and MIT have identified the resistance mechanisms of malignant melanoma cells, which lead in two out of three cases to failure of treatment with immunotherapy.
- By combining CRISPR gene editing and RNA and protein sequencing, researchers have identified new mechanisms of cancer cell resistance to immunotherapy.
- One of these resistances is associated with the CD58 gene. But by reactivating it, it is possible to overcome the cells’ resistance to immunotherapy treatment.
With nearly 80,000 new cases each year in France, skin cancers are the most frequent cancers. Among them, 15,400 melanomas are identified every year. When detected early, this serious form of cancer can be effectively treated with surgery and, in recent years, with immunotherapy.
Proposed in addition to surgery, immunotherapy is however not a miracle treatment, since it fails or ceases to work in two thirds of patients with melanoma.
Identify mechanisms of resistance to immunotherapy
In a new study published in Nature Genetics, researchers from Columbia and MIT explain that they have developed a new technique to discover the “tricks” used by cancer cells to escape immunotherapies. In particular, they discovered previously unknown resistance mechanisms in melanoma to immune checkpoint inhibitors, a powerful and widely used class of immunotherapy drugs.
What are immune checkpoint inhibitors? These are drugs that work by blocking specific checkpoint proteins for immune system cells (T-lymphocytes) to attack and destroy cancer cells. In a third of patients, this class of drugs can cure metastatic melanoma, “even at a stage when the disease has spread throughout the body, explains Professor Benjamin Izar, lead author of the study. So the question is what happens to the other two-thirds of patients. What are the mechanisms of intrinsic or adaptive drug resistance?
250 genes involved in resistance to immunotherapy
To find out, the researchers developed a tool that combines two technologies: CRISPR gene editing and single-cell RNA and protein sequencing.
Using CRISPR, the researchers first inactivated the 250 genes of metastatic melanoma cells previously identified as allowing them to escape immunotherapy. They knocked them out one at a time but in bulk, to create a mix of 250 batches of melanoma cells, each with a different mutation. These “modified” cancer cells were then exposed to T-lymphocytes, which are triggered by the control inhibitors in patients.
Cancer cells that resisted T-cell attack were isolated and protein profiling was performed using RNA sequencing to provide a high-resolution “molecular map” of several gene disruptions leading to immune escape.
The key role of the CD58 gene
In total, nearly 250,000 cells were analyzed. The analysis identified new mechanisms of resistance to immunotherapy, including one involving the CD58 gene. “Our data suggest that loss of CD58 in melanoma cells confers immune escape through three potential mechanisms: impaired T-cell activation, reduced ability of T-cells to enter the tumor, and increased production of PD-L1, details Professor Johannes C. Melms. As the CD58 gene is not mutated per se, but simply turned off, this raises the possibility that therapies that activate it may overcome drug resistance in some patients.”
Now, researchers plan to develop therapies to improve response to immunotherapies based on this finding. “CD58 is just one of many genes that merit further investigation”concludes Professor Izar.
