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    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 (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

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