Claudin-low bladder tumors are immune infiltrated and actively immune suppressed.

We report the discovery of a claudin-low molecular subtype of high-grade bladder cancer that shares characteristics with the homonymous subtype of breast cancer. Claudin-low bladder tumors were enriched for multiple genetic features including increased rates of RB1, EP300, and NCOR1 mutations; increased frequency of EGFR amplification; decreased rates of FGFR3, ELF3, and KDM6A mutations; and decreased frequency of PPARG amplification. While claudin-low tumors showed the highest expression of immune gene signatures, they also demonstrated gene expression patterns consistent with those observed in active immunosuppression. This did not appear to be due to differences in predicted neoantigen burden, but rather was associated with broad upregulation of cytokine and chemokine levels from low PPARG activity, allowing unopposed NFKB activity. Taken together, these results define a molecular subtype of bladder cancer with distinct molecular features and an immunologic profile that would, in theory, be primed for immunotherapeutic response.

[1]  Torben F. Ørntoft,et al.  Identifying distinct classes of bladder carcinoma using microarrays , 2003, Nature Genetics.

[2]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  V. Reuter,et al.  CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma , 2007, Proceedings of the National Academy of Sciences.

[4]  A. Nobel,et al.  Statistical Significance of Clustering for High-Dimension, Low–Sample Size Data , 2008 .

[5]  Howard Y. Chang,et al.  Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells , 2009, Proceedings of the National Academy of Sciences.

[6]  Jason I. Herschkowitz,et al.  Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer , 2010, Breast Cancer Research.

[7]  M. Knowles,et al.  Bladder cancer or bladder cancers? Genetically distinct malignant conditions of the urothelium. , 2010, Urologic oncology.

[8]  E. Tartour,et al.  Immune infiltration in human cancer: prognostic significance and disease control. , 2011, Current topics in microbiology and immunology.

[9]  Jens-Peter Volkmer,et al.  Three differentiation states risk-stratify bladder cancer into distinct subtypes , 2012, Proceedings of the National Academy of Sciences.

[10]  J. Peters,et al.  The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention , 2012, Nature Reviews Cancer.

[11]  Mårten Fernö,et al.  A Molecular Taxonomy for Urothelial Carcinoma , 2012, Clinical Cancer Research.

[12]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[13]  M. Ittmann,et al.  Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. , 2012, Cancer cell.

[14]  Charles M. Perou,et al.  Characterization of cell lines derived from breast cancers and normal mammary tissues for the study of the intrinsic molecular subtypes , 2011, Breast Cancer Research and Treatment.

[15]  M. Ni,et al.  Inference of high resolution HLA types using genome-wide RNA or DNA sequencing reads , 2014, BMC Genomics.

[16]  Xiaoping Su,et al.  Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer , 2014, Nature Reviews Urology.

[17]  Benjamin J. Raphael,et al.  Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin , 2014, Cell.

[18]  K. Baggerly,et al.  Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. , 2014, Cancer cell.

[19]  R. Emerson,et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance , 2014, Nature.

[20]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of urothelial bladder carcinoma , 2014, Nature.

[21]  S. Waldman,et al.  Selective antigen‐specific CD4+ T‐cell, but not CD8+ T‐ or B‐cell, tolerance corrupts cancer immunotherapy , 2014, European journal of immunology.

[22]  Charles M. Perou,et al.  Prognostic B-cell Signatures Using mRNA-Seq in Patients with Subtype-Specific Breast and Ovarian Cancer , 2014, Clinical Cancer Research.

[23]  The Cancer Genome Atlas Research Network.  Comprehensive molecular characterization of urothelial bladder carcinoma , 2014, Nature.

[24]  Lixia Diao,et al.  Metastasis is regulated via microRNA-200/ZEB1 axis control of tumor cell PD-L1 expression and intratumoral immunosuppression , 2014, Nature Communications.

[25]  P. Hegde,et al.  MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer , 2014, Nature.

[26]  Xavier Paoletti,et al.  EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype , 2014, Science Translational Medicine.

[27]  Scott D. Brown,et al.  Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival , 2014, Genome research.

[28]  Katherine A. Hoadley,et al.  Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology , 2014, Proceedings of the National Academy of Sciences.

[29]  J. Wolchok,et al.  Genetic basis for clinical response to CTLA-4 blockade in melanoma. , 2014, The New England journal of medicine.

[30]  K. Cibulskis,et al.  Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. , 2014, Blood.

[31]  S. Gabriel,et al.  Genomic correlates of response to CTLA-4 blockade in metastatic melanoma , 2015, Science.

[32]  N. Hacohen,et al.  Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity , 2015, Cell.

[33]  Jaime Rodriguez-Canales,et al.  A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition , 2015, Clinical Cancer Research.

[34]  T. Schumacher,et al.  Neoantigens in cancer immunotherapy , 2015, Science.

[35]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[36]  J. Slotta-Huspenina,et al.  The prognostic effect of tumour-infiltrating lymphocytic subpopulations in bladder cancer , 2016, World Journal of Urology.

[37]  Yusuke Nakamura,et al.  Low T-cell Receptor Diversity, High Somatic Mutation Burden, and High Neoantigen Load as Predictors of Clinical Outcome in Muscle-invasive Bladder Cancer. , 2016, European urology focus.