



Checkpoint immunotherapy drugs have seen a surge in their adoption as their effectiveness in treating various cancers continues to provide clinical success. Yet, one type of persistent tumor has remained relatively intractable to immunotherapeutic interventions—bladder cancer. However now, a team of researchers led by investigators at the Vancouver Prostate Centre and Vancouver Coastal Health Research Institute (VCHRI) has just released new findings that offer a possible explanation for why this new type of cancer treatment hasn't been working as expected.

Results from the new study—published today in Nature Communications in an article entitled “Evasion of Immunosurveillance by Genomic Alterations of PPARγ/RXRα in Bladder Cancer”—finds that checkpoint immunotherapy, which is designed to activate the immune system, is not effective on some bladder cancers because there are no immune cells in those tumors. The new findings explain what is occurring at the cellular level to prevent the immune cells from getting into the tumor. Moreover, the research team is optimistic that their data will open up new avenues of research that will direct scientists toward developing a combination therapy that could be more effective.

“It's been a mystery for decades as to how tumors escape the immune system,” explained co-senior study investigator Mads Daugaard, Ph.D., assistant professor of urologic science at the University of British Columbia and a senior scientist at the Vancouver Prostate Centre and VCHRI. “We've identified a cellular signaling pathway that regulates whether the body's immune cells are allowed to infiltrate the tumor.”

Currently, bladder cancer accounts for about 5% of all new cancers in the U.S. and is the fifth most common cancer in Canada. Furthermore, there is only one line of chemotherapy available, cisplatin-based therapy, for invasive tumors. Once cancers become resistant, only checkpoint immunotherapy is approved as a second-line treatment.

Atezolizumab, an anti-programmed death-ligand 1 (anti-PDL1) antibody drug, strengthens the body's immune response and recently became the first new bladder cancer drug to be approved in more than 20 years. While initial results were very promising, subsequent clinical trials have shown that only one in five patients showed an objective response to treatment, which has perplexed researchers, until now.

In the current study, the researchers found that some invasive bladder cancer tumors block the immune cells from accessing it by activating a cell signaling pathway called the peroxisome proliferator-activated receptor gamma (PPARγ) pathway.

The authors reported in the current study “that the PPARγ/RXRα [retinoid X receptor alpha] pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC [muscle-invasive bladder cancer]. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγHigh/RXRαS427F/Y impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies.”

“With this pathway, the tumors close the door to the immune system,” Dr. Daugaard added. “Without immune cells in the tumor, checkpoint immunotherapy has little effect. Now we know what door the tumors are closing, and we can, therefore, focus our efforts on breaking down that door and let the immune system back in.”

The researchers have taken the first steps to develop a drug that is capable of targeting the PPARγ pathway. The rationale is to use such a drug in combination with checkpoint immunotherapy treatment.

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



























