title: Assessing microenvironment immunogenicity using tumor specimen exomes: Co-detection of TcR-α/β V(D)J recombinations correlates with PD-1 expression.
abstract: T-cell receptor (TcR) recombinations can be recovered from tumor specimen, whole exome sequences (WXS) files. However, it is not yet clear how these recombinations represent lymphocytes or an anti-tumor immune response. Here we report the identification of productive TcR-β recombinations in WXS files representing primary and metastatic melanoma. The recombinations are identifiable in about 20% of the cancer genome atlas melanoma samples. This frequency of detection is lower than the frequency of TcR-α VJ recombinations, consistent with the occurrence of biallelic TcR-α recombinations and possibly consistent with the fact that only one junctional recombination is required for TcR-α whereas two recombinations are required to form a TcR-β gene. Nevertheless, the ratio of productive TcR-β to unproductive TcR-β samples, in comparison to the ratio of productive to unproductive TcR-α or TcR-γ positive-samples, is very high. This result indicates that detection of a productive TcR-β VDJ recombination represents a comparatively high standard for potential antigen binding capacity, when employing a tumor specimen exome file for the assessment. Additionally, PD-1 expression and antigen presentation functions correlated with the co-detection of TcR-α and -β recombinations (e.g., p < 0.0004), suggesting that co-detection of TcR-α and -β recombinations represents an anti-melanoma response that has been blunted by the advent of PD-1 expression. We further show that the algorithm for detecting the TcR-β VDJ recombinations is applicable to exome files generated from mouse tissue, thus providing for opportunities to develop empirical paradigms for interpreting the identification of TcR V(D)J recombinations in tissue resident lymphocytes.
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL.
authors.forename: Yaping N
authors.initials: YN
authors.lastname: Tu
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL.
authors.forename: Wei Lue
authors.initials: WL
authors.lastname: Tong
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL.
authors.forename: Mohammad D
authors.initials: MD
authors.lastname: Samy
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL.
authors.forename: John M
authors.initials: JM
authors.lastname: Yavorski
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL.|Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: George
authors.identifier: 0000-0003-1664-0996
authors.initials: G
authors.lastname: Blanck
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics*; D001483:Base Sequence; D059472:Exome / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics*; D060152:V(D)J Recombination / Q000235:genetics*
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta
keywords: PD-1; T-cell receptor recombinations; antigen processing; melanoma; the cancer genome atlas; tumor specimen exomes