Immunosuppressive Myeloid Cells Induce Nitric Oxide-Dependent DNA Damage and p53 Pathway Activation in CD8+ T Cells.
Cancer Immunol Res
; 9(4): 470-485, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33514509
ABSTRACT
Tumor-infiltrating myeloid-derived suppressor cells (MDSC) are associated with poor survival outcomes in many human cancers. MDSCs inhibit T cell-mediated tumor immunity in part because they strongly inhibit T-cell function. However, whether MDSCs inhibit early or later steps of T-cell activation is not well established. Here we show that MDSCs inhibited proliferation and induced apoptosis of CD8+ T cells even in the presence of dendritic cells (DC) presenting a high-affinity cognate peptide. This inhibitory effect was also observed with delayed addition of MDSCs to cocultures, consistent with functional data showing that T cells expressed multiple early activation markers even in the presence of MDSCs. Single-cell RNA-sequencing analysis of CD8+ T cells demonstrated a p53 transcriptional signature in CD8+ T cells cocultured with MDSCs and DCs. Confocal microscopy showed induction of DNA damage and nuclear accumulation of activated p53 protein in a substantial fraction of these T cells. DNA damage in T cells was dependent on the iNOS enzyme and subsequent nitric oxide release by MDSCs. Small molecule-mediated inhibition of iNOS or inactivation of the Nos2 gene in MDSCs markedly diminished DNA damage in CD8+ T cells. DNA damage in CD8+ T cells was also observed in KPC pancreatic tumors but was reduced in tumors implanted into Nos2-deficient mice compared with wild-type mice. These data demonstrate that MDSCs do not block early steps of T-cell activation but rather induce DNA damage and p53 pathway activation in CD8+ T cells through an iNOS-dependent pathway.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
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Linfócitos T CD8-Positivos
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Óxido Nítrico Sintase Tipo II
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Células Supressoras Mieloides
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Óxido Nítrico
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Immunol Res
Ano de publicação:
2021
Tipo de documento:
Article