Evasion of immunosurveillance by genomic alterations of PPAR?/RXR? in bladder cancer.

ABSTRACT: Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPAR?/RXR? pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXR? at serine 427 (S427F/Y), through conformational activation of the PPAR?/RXR? heterodimer, and focal amplification/overexpression of PPAR? converge to modulate PPAR?/RXR?-dependent transcription programs. Immune cell-infiltration is controlled by activated PPAR?/RXR? that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPAR?High/RXR?S427F/Y impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPAR? or RXR? and pharmacological inhibition of PPAR? significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic "immuno-oncogenes" that modulate the immune microenvironment of cancer.Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease. Here the authors characterize diverse genetic alterations in MIBC that convergently lead to constitutive activation of PPARgamma/RXRalpha and result in immunosurveillance escape by inhibiting CD8+ T-cell recruitment.

SUBMITTER: Korpal M 

PROVIDER: S-EPMC5524640 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature