Genomic research may explain resistance to immunotherapy

New research characterizing the molecular mechanisms regulating immune cell infiltration into the luminal subtype of muscle-invasive bladder cancer may explain resistance to treatment with immune checkpoint blockade and suggest a target for improving therapeutic response.

New research characterizing the molecular mechanisms regulating immune cell infiltration into the luminal subtype of muscle-invasive bladder cancer (MIBC) may explain resistance to treatment with immune checkpoint blockade and suggest a target for improving therapeutic response.

In a recently published paper (Nature Communications 2017; 8:103), Mads Daugaard, MSc, PhD, and colleagues described their work identifying genomic activation of the PPARγ/RXRα pathway secondary to hotspot mutations in RXRA or gene amplifications in PPARG (the gene encoding PPARγ) as the potential cause for failed host immunosurveillance and immunotherapy resistance.

After finding that PPARG overexpression and RXRA mutations were significantly enriched in the luminal subtype of MIBC and resulted in PPARγ pathway activation, they looked for correspondence with the immune signature of the tumors, knowing that PPARG has immunosuppressive activity. The analyses showed that tumors with high expression of PPARG or with RXRA mutations were nearly devoid of infiltrating CD8+ T cells. The authors also determined that inhibition of the host immune response was mediated through suppressed expression and secretion of proinflammatory cytokines.

Studies performed in both cell lines and animal models showed that the efficacy of checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies was reduced if the tumors expressed mutated RXRA.

Next: Dr. Daugaard discusses findings

“Based on our research so far, we are fairly certain that immune evasion mediated by the PPARγ/RXRα pathway affects patient responses to checkpoint inhibitor therapy for MIBC. However, because all of the checkpoint inhibitors that are approved for treating bladder cancer act via the PD-1/PD-L1 pathway, we are now repeating our experiments using an antiPD-1 inhibitor in the context of PPARγ over-expression,” said Dr. Daugaard, of the University of British Columbia, Vancouver.

“In addition, we have launched a drug development program at the Vancouver Prostate Centre to develop a small molecule targeting PPARG as a possible therapeutic approach to restore immunosurveillance and increase response to checkpoint immunotherapy.”

Dr. Daugaard, who is also a senior scientist at the Vancouver Prostate Centre, noted that the small molecule drug development program at the Vancouver Prostate Centre has a history of success. In 2015, it licensed a novel small molecule anti-androgen receptor agent to Roche for commercial development as a treatment for drug-resistant prostate cancer.

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Meanwhile, Dr. Daugaard and colleagues are engaged in several other lines of research involving PPARγ/RXRα. Whether activation of the PPARγ/RXRα heterodimer affects immune inhibition mechanisms of other tumors or is a phenomenon that is specific to luminal bladder cancer is one of the questions they are investigating. Dr. Daugaard told Urology Times that so far, overexpression of PPARG has not been found in prostate cancer, but its potential presence has not yet been ruled out, and analyses of renal cell carcinoma are also ongoing.

In addition, they are trying to determine whether the RXRA hotspot mutations are innate or acquired after initiation of treatment for cancer.

“The answer to this question has been unclear because the genomics databases that we have investigated include specimens from both treated and untreated patients. Analyses of a lot more samples will be needed,” Dr. Daugaard said.