title: Altered Expression and Splicing of ESRP1 in Malignant Melanoma Correlates with Epithelial-Mesenchymal Status and Tumor-Associated Immune Cytolytic Activity.
abstract: Melanoma is one of the major cancer types for which new immune-based cancer treatments have achieved promising results. However, anti-PD-1 and anti-CTLA-4 therapies are effective only in some patients. Hence, predictive molecular markers for the development of clinical strategies targeting immune checkpoints are needed. Using The Cancer Genome Atlas (TCGA) RNAseq data, we found that expression of ESRP1, encoding a master splicing regulator in the epithelial-mesenchymal transition (EMT), was inversely correlated with tumor-associated immune cytolytic activity. That association holds up across multiple TCGA tumor types, suggesting a link between tumor EMT status and infiltrating lymphocyte activity. In melanoma, ESRP1 mainly exists in a melanocyte-specific truncated form transcribed from exon 13. This was validated by analyzing CCLE cell line data, public CAGE data, and RT-PCR in primary cultured melanoma cell lines. Based on ESRP1 expression, we divided TCGA melanoma cases into ESRP1-low, -truncated, and -full-length groups. ESRP1-truncated tumors comprise approximately two thirds of melanoma samples and reside in an apparent transitional state between epithelial and mesenchymal phenotypes. ESRP1 full-length tumors express epithelial markers and constitute about 5% of melanoma samples. In contrast, ESRP1-low tumors express mesenchymal markers and are high in immune cytolytic activity as well as PD-L2 and CTLA-4 expression. Those tumors are associated with better patient survival. Results from our study suggest a path toward the use of ESRP1 and other EMT markers as informative biomarkers for immunotherapy. Cancer Immunol Res; 4(6); 552-61. ©2016 AACR.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Ludwig Collaborative Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland. Orygen Biotecnologia, SA., São Paulo, SP, Brazil.
authors.forename: Otavia L
authors.initials: OL
authors.lastname: Caballero
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, New York.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, New York.
authors.forename: Calvin
authors.initials: C
authors.lastname: Lin
authors.affiliation: Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center, University of Lausanne, Switzerland, Lausanne, Switzerland.
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.affiliation: Cancer Immunobiology Laboratory, Olivia Newton-John Cancer Research Institute, Victoria, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Behren
authors.affiliation: Cancer Immunobiology Laboratory, Olivia Newton-John Cancer Research Institute, Victoria, Australia.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Cebon
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.affiliation: Ludwig Cancer Research, New York, New York. qi.zhao@regeneron.com rls@licr.org.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Strausberg
authors.affiliation: Ludwig Collaborative Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland. Regeneron Pharmaceuticals Inc., Tarrytown, New York. qi.zhao@regeneron.com rls@licr.org.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D030541:Databases, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; C539364:ESRP1 protein, human; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins