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Control point drugs have revolutionized the treatment of melanoma and other cancers by releasing the immune system to attack tumors. But medications do not work for half of the patients, even if they are associated with other cancer treatments.
Two separate research groups have now discovered different mechanisms of resistance to immuno-oncological drugs. One relates to the intestinal microbiome, while the other is related to vesicles produced by cancer cells.
First, a global consortium of 40 scientists led by the Sanford Burnham Prebys Cancer Center published a study demonstrating that the intestinal microbiome orchestrates the immune system's response to cancer. They published their observations in Nature Communications.
The team led by Sanford Burnham made this discovery by working with mice designed to be devoid of finger protein RING 5 (RNF5), a gene that normally works to remove damaged proteins from cells. These mice developed a strong immune response to melanoma. The researchers used bioinformatics technology to identify 11 abundant bacterial strains in the intestines of animals. They then transferred the bacteria to normal mice and found that the mice also induced a strong immune response to melanoma in these animals.
The researchers mapped the immune components active in the intestine and found that a signaling pathway called an unreduced protein response (RPU) was reduced when immune cells were activated. They then studied tumor samples from people who received control point inhibitors and found that the reduction in UPR expression correlated with a good response to treatment.
The results "identify a set of bacterial strains that could activate anti-tumor immunity and biomarkers that can be used to stratify people with melanoma for treatment with selected control point inhibitors," he said. Ze & # 39; Ron Ronai, Ph.D., in a statement.
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The second study, conducted by a team at the University of California at San Francisco, focused on the PD-L1 protein, a target of some drugs that inhibit checkpoints. Normally, checkpoint inhibitors work by recognizing PD-L1 on the surface of cancer cells, then interfering with it or with the corresponding PD-1 protein. UCSF researchers found that in some patients, PD-L1 was moving throughout the body, inhibiting immune cells before they could reach cancer.
In these patients, PD-L1 results in exosomes, which are vesicles from cancer cells and moving in the bloodstream to the lymph nodes, the UCSF team discovered. There, they "disarm" the immune cells, so they can not attack cancer. They published their findings in the journal Cell.
The reason patients sometimes do not respond to PD-L1 inhibitors is that their cancers do not produce enough protein. But UCSF researchers have shown that "the protein was actually manufactured at one time and that it was not degraded," said lead author Robert Blelloch, MD, Ph.D., a professor of urology at UCSF. "It is at this point that we examined the exosomes and found the missing PD-L1."
In a second experiment, the UCSF team used the CRISPR gene modification technology to remove two genes required for the production of exosomes from cancer cells. Mice that received these cells had more activated immune cells in their lymph nodes than animals with unmodified cancer cells.
They then treated a murine model of colorectal cancer with a combination of a PD-L1 inhibitor and a drug preventing the formation of exosomes. These mice survived longer than animals treated with either drug alone.
The Blelloch team plans to conduct further studies with the ultimate goal of developing a "tumor cell vaccine" to help patients who are not currently responding to checkpoint inhibitors.
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