RESUMO
γδ T cells in human solid tumors remain poorly defined. Here, we describe molecular and functional analyses of T-cell receptors (TCR) from tumor-infiltrating γδ T lymphocytes (γδ TIL) that were in direct contact with tumor cells in breast cancer lesions from archival material. We observed that the majority of γδ TILs harbored a proinflammatory phenotype and only a minority associated with the expression of IL17. We characterized TCRγ or TCRδ chains of γδ TILs and observed a higher proportion of Vδ2+ T cells compared with other tumor types. By reconstructing matched Vδ2- TCRγ and TCRδ pairs derived from single-cell sequencing, our data suggest that γδ TILs could be active against breast cancer and other tumor types. The reactivity pattern against tumor cells depended on both the TCRγ and TCRδ chains and was independent of additional costimulation through other innate immune receptors. We conclude that γδ TILs can mediate tumor reactivity through their individual γδ TCR pairs and that engineered T cells expressing TCRγ and δ chains derived from γδ TILs display potent antitumor reactivity against different cancer cell types and, thus, may be a valuable tool for engineering immune cells for adoptive cell therapies.
Assuntos
Imunoterapia Adotiva/métodos , Leucócitos Mononucleares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T gama-delta/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapiaAssuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Receptores de Antígenos , Análise de Sequência de RNA/métodos , Algoritmos , Animais , Bases de Dados Genéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Melanoma/química , Melanoma/genética , Melanoma/mortalidade , Camundongos , RNA/análise , RNA/genética , Receptores de Antígenos/análise , Receptores de Antígenos/genética , Receptores de Antígenos/metabolismo , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Summary. We analyzed several prokaryotic and eukaryotic genomes looking for the periodicity sequences availability and employing a new mathematical method. The method envisaged using the random position weight matrices and dynamic programming. Insertions and deletions were allowed inside periodicities, thus adding a novelty to the results we obtained. A periodicity length, one of the key periodicity features, varied from 2 to 50 nt. Totally over 60,000 periodicity sequences were found in 15 genomes including some chromosomes of the H. sapiens (partial), C. elegans, D. melanogaster, and A. thaliana genomes.
Assuntos
Genoma , Mutação INDEL/genética , Análise de Sequência de DNA , Animais , Arabidopsis/genética , Caenorhabditis elegans/genética , Cromossomos/genética , Drosophila melanogaster/genética , Humanos , Modelos Teóricos , Células ProcarióticasRESUMO
Transfer RNA (tRNA)-like sequences were searched for in the nine basic taxonomic divisions of GenBank-121 (viruses, phages, bacteria, plants, invertebrates, vertebrates, rodents, mammals, and primates) by an original program package implementing a dynamic profile alignment approach for the genetic texts' analysis, in using 22 profiles of tRNAs of different isotypes. In total, 175,901 previously unknown tRNA-like sequences were revealed. The locations of the tRNA-likes were considered over the regions whose functional meaning is described by standard Feature Keys in GenBank. Many regions containing the tRNA-like sequences were recognized as known repeats. A mode of distribution of the tRNA-like sequences in a genome was proposed as expansion in a content of the various transposable elements. An analysis of the integrity of RNA polymerase III inner promoters in the tRNA-like sequences over the GenBank divisions has shown a high possibility of generating new copies of short interspersed nuclear element (SINE) repeats in all divisions, excepting primates. The numerous tRNA-likes found in the regions of RNA polymerase II promoters have suggested an adaptation of RNA polymerase III promoter to a binding of RNA polymerase II.
