Checkpoint-inhibiting drugs have revolutionized the treatment of melanoma and other cancers by freeing up the immune system to attack tumors. But the medicines don’t work for as many as half of patients, even when they’re combined with other cancer treatments.
Now, two separate research groups have uncovered different mechanisms of immuno-oncology drug resistance. One involves the gut microbiome, while the other is related to vesicles that are produced by cancer cells.
First, a worldwide consortium of 40 scientists led by Sanford Burnham Prebys released a study demonstrating that the gut microbiome orchestrates the immune system’s response to cancer. They published their observations in the journal Nature Communications.
The Sanford Burnham Prebys-led team made the discovery by working with mice engineered to lack RING finger protein 5 (RNF5), a gene that normally works to clear damaged proteins from cells. These mice mounted a strong immune response to melanoma, so the researchers used bioinformatics technology to identify 11 bacterial strains that were plentiful in the animals’ guts. They then transferred the bacteria to normal mice and found it also induced a strong immune response to melanoma in those animals.
The researchers mapped out the immune components that were active in the gut, and they discovered that a signaling pathway called the unfolded protein response (UPR) was reduced when immune cells were activated. Then they studied tumor samples from people who had received checkpoint inhibitors, and they found reduced UPR expression correlated with a good response to treatment.
The findings “identify a collection of bacterial strains that could turn on anti-tumor immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors," said senior author and Sanford Burnham Prebys professor Ze'ev Ronai, Ph.D., in a statement.
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The second study, from a team at the University of California, San Francisco (UCSF), focused on the protein PD-L1, the target of some checkpoint-inhibiting drugs. Normally, checkpoint inhibitors work by recognizing PD-L1 on the surface of cancer cells and then interfering either with it or the related protein PD-1. The UCSF researchers discovered that in some patients, PD-L1 travels throughout the body, inhibiting immune cells before they can reach the cancer.
In those patients, the PD-L1 ends up in exosomes, which are vesicles that come from cancer cells and travel in the bloodstream to the lymph nodes, the UCSF team discovered. While there, they “disarm” the immune cells, so they’re unable to launch an attack against the cancer. They published their findings in the journal Cell.
The prevailing view of why patients sometimes don’t respond to PD-L1 inhibitors is that their cancers are not making enough of the protein. But the UCSF researchers showed "the protein was in fact being made at some point, and that it wasn't being degraded,” senior author Robert Blelloch, M.D,. Ph.D., professor of urology at UCSF, said in a statement. “That's when we looked at exosomes and found the missing PD-L1."
In a second experiment, the UCSF team used the gene-editing technology CRISPR to delete two genes necessary for exosome production from cancer cells. Mice that received those cells had more activated immune cells in their lymph nodes than did animals that got unedited cancer cells.
They then treated a mouse model of colorectal cancer with a combination of a PD-L1 inhibitor and a drug that prevents exosomes from forming. Those mice survived longer than animals treated with either drug alone did.
Blelloch’s team plans to conduct further studies, with the ultimate goal of developing a “tumor cell vaccine” to help patients who don’t currently respond to checkpoint inhibitors.