Mechanism for Checkpoint Inhibitor Resistance Identified in Invasive Bladder Cancer

Researchers have identified a cellular signaling pathway that when activated by mutations may prevent immune cells from infiltrating bladder tumors, thus making the cancer resistant to immune checkpoint inhibitors.

According to the study, published in Nature Communications, immunotherapies such as the checkpoint inhibitor anti-programmed death-ligand 1 (PD-L1) have shown promising results in treating aggressive tumors like muscle-invasive bladder cancer. However, they are not reliably effective, as the majority of patients show no response to the treatment, leading researchers to investigate the specific genomic mutations and cell pathways that may contribute to immunotherapy resistance.

The study authors analyzed cancer genome alterations gathered from genomic databases, including The Cancer Genome Atlas, and identified several genetic alterations prominently expressed in bladder cancer patients. After modeling the transcriptional impact of each of these mutations, they determined that overexpression of some locations on retinoid X receptor alpha (RXRα^S427F/Y) and/or peroxisome proliferator-activate receptor gamma (PPARγ) can activate the PPARγ pathway. This pathway, they found, suppresses the secretion of cytokines from cancer cells, creating an immunosuppressive environment that inhibits the chemokines that have been linked to better response to anti-PD-L1 treatment in patients with bladder cancer . Essentially, this pathway determines whether the body’s immune cells, activated by the checkpoint inhibitors, can invade the bladder tumor.

“Collectively, our findings suggest that the PPARγ/RXRα^S427F/Y pathway in tumor cells might influence the activity/localization of host immune cells and potentially blunt response to immunotherapy,” the study summarized.

The finding could have important implications for reversing immunotherapy resistance. Further analyses described in the study suggest that targeting the pathway in question “may serve as a viable therapeutic node for activating immunosurveillance,” which could boost patients’ response to immune checkpoint inhibitors.

According to a media statement from the University of British Columbia (UBC), knowing that the pathway allows the tumor to “close the door to the immune system” will enable scientists to concentrate their “efforts on breaking down that door and let the immune system back in,” in the words of co-author Mads Daugaard, PhD, assistant professor at UBC and senior research scientist at the Vancouver Prostate Centre.

“Further understanding of the regulatory mechanisms and deeper identification of relevant pathways/targets in specific tumors should pave the way for the next-generation cancer immunotherapies,” the researchers wrote in the article.

In the meantime, Daugaard and his colleagues are working to create a drug to be given in combination with checkpoint inhibitors that would target the PPARγ pathway.

“The most efficient way to combat a cancer would be to have the immune system take care of it itself,” said Daugaard in the press release. “This is ultimately what we want to achieve.”