Two separate studies have uncovered insights into why checkpoint-inhibiting immune-oncology (IO) drugs only work for a minority of patients, even when combined with other treatments. The first study uncovered a resistance mechanism within the gut microbiome, while the other relates to cancer cell-produced vesicles.

The first study, led by the Sanford Burnham Prebys Cancer Center, showed that the gut microbiome manages the response of the immune system to cancer. Mice were engineered without RING finger protein 5, a gene which removes damaged proteins from cells, and were found to have a strong immune response to melanoma. When 11 identified bacterial strains prevalent in their guts were transferred to normal mice, they too developed a strong resistance to melanoma.

Further research found that a signalling pathway in the gut called the unfolded protein response (UPR) lessened with the activation of immune cells. The researchers then studied tumor samples from individuals who had received checkpoint inhibitors, with findings showing that reduced UPR expression was generally linked with a healthy response to treatment.

The second study, conducted by scientists from the University of California, looked at the PD-L1 protein, which is targeted by some IO drugs which recognise the protein on cancer cell surfaces and interfere with it. The scientists found that PD-L1 travels through some patients’ bodies, inhibiting immune cells before they can reach the cancer.

In these cases PD-L1 travel into exosomes to the lymph nodes, where they interfere with immune cells and stop them from launching to attack the cancer.

The California scientists said they intend now to conduct further tests and to develop a tumor cell vaccine to help individuals who at the moment aren’t responding to checkpoint inhibitors.