Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
1.
Cell ; 179(1): 219-235.e21, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31522890

RESUMO

Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade.


Assuntos
Heterogeneidade Genética/efeitos da radiação , Melanoma/genética , Melanoma/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Raios Ultravioleta/efeitos adversos , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Humanos , Linfócitos do Interstício Tumoral , Melanoma/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Mutação/efeitos da radiação , Filogenia , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
2.
Mol Microbiol ; 97(5): 898-910, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26031711

RESUMO

The natural role of the conserved bacterial anticodon nuclease (ACNase) RloC is not known, but traits that set it apart from the homologous phage T4-excluding ACNase PrrC could provide relevant clues. PrrC is silenced by a genetically linked DNA restriction-modification (RM) protein and turned on by a phage-encoded DNA restriction inhibitor. In contrast, RloC is rarely linked to an RM protein, and its ACNase is regulated by an internal switch responsive to double-stranded DNA breaks. Moreover, PrrC nicks the tRNA substrate, whereas RloC excises the wobble nucleotide. These distinctions suggested that (i) T4 and related phage that degrade their host DNA will activate RloC and (ii) the tRNA species consequently disrupted will not be restored by phage tRNA repair enzymes that counteract PrrC. Consistent with these predictions we show that Acinetobacter baylyi RloC expressed in Escherichia coli is activated by wild-type phage T4 but not by a mutant impaired in host DNA degradation. Moreover, host and T4 tRNA species disrupted by the activated ACNase were not restored by T4's tRNA repair system. Nonetheless, T4's plating efficiency was inefficiently impaired by AbaRloC, presumably due to a decoy function of the phage encoded tRNA target, the absence of which exacerbated the restriction.


Assuntos
Bacteriófago T4/genética , Quebras de DNA , RNA de Transferência/metabolismo , Ribonucleases/metabolismo , Acinetobacter/genética , Acinetobacter/virologia , Sequência de Aminoácidos , Bacteriófago T4/crescimento & desenvolvimento , Bacteriófago T4/metabolismo , Bacteriófago T4/patogenicidade , Ativação Enzimática , Escherichia coli/genética , Escherichia coli/virologia , Proteínas de Escherichia coli/genética , RNA de Transferência/genética , Ribonucleases/genética
3.
Nat Commun ; 11(1): 896, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060274

RESUMO

Predicting the outcome of immunotherapy treatment in melanoma patients is challenging. Alterations in genes involved in antigen presentation and the interferon gamma (IFNγ) pathway play an important role in the immune response to tumors. We describe here that the overexpression of PSMB8 and PSMB9, two major components of the immunoproteasome, is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients. We study the mechanism underlying this connection by analyzing the antigenic peptide repertoire of cells that overexpress these subunits using HLA peptidomics. We find a higher response of patient-matched tumor infiltrating lymphocytes against antigens diferentially presented after immunoproteasome overexpression. Importantly, we find that PSMB8 and PSMB9 expression levels are much stronger predictors of melanoma patients' immune response to checkpoint inhibitors than the tumors' mutational burden. These results suggest that PSMB8 and PSMB9 expression levels can serve as important biomarkers for stratifying melanoma patients for immune-checkpoint treatment.


Assuntos
Melanoma/imunologia , Melanoma/terapia , Complexo de Endopeptidases do Proteassoma/genética , Apresentação de Antígeno , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/imunologia , Humanos , Imunoterapia , Interferon gama/genética , Interferon gama/imunologia , Melanoma/diagnóstico , Melanoma/genética , Prognóstico , Complexo de Endopeptidases do Proteassoma/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA