Abstract
Oncogenic T-cell signaling upregulates PD-1, which increases PTEN expression to suppress oncogenesis.
Major finding: Oncogenic T-cell signaling upregulates PD-1, which increases PTEN expression to suppress oncogenesis.
Clinical relevance: Genetic alterations in PDCD1 (encoding PD-1) occur in a subset of patients with T-cell lymphoma.
Impact: Strategies to inhibit PD-1 may have the potential to reactivate T cells with oncogenic alterations.
T-cell non-Hodgkin lymphomas (NHL) are aggressive malignancies that arise from peripheral T cells that frequently harbor gain-of-function mutations in T-cell receptor (TCR) signaling molecules that drive oncogenesis. However, it is unclear if T cells have tumor suppressors that can counteract the oncogenic events. To address this question, Wartewig and colleagues developed a mouse model of human T-cell NHL by introducing a CD4-Cre–inducible patient-derived ITK–SYK fusion gene, which is generated by a recurrent chromosomal translocation in T-cell lymphoma. These ITK–SYKCD4-Cre mice develop fully penetrant aggressive T-cell lymphomas that recapitulate the human disease. A single pulse of Cre activity to induce ITK–SYK expression in single T cells was sufficient to induce rapid expansion of ITK–SYKCD4-Cre lymphocytes, but the response was short-lived, indicative of cell-intrinsic tumor suppressive mechanisms. A genome-wide forward genetic screen using the piggyBac transposition system for in vivo mutagenesis identified PDCD1 (which encodes PD-1) as a potential tumor suppressor in T-cell lymphoma. A meta-analysis of five published studies showed that PDCD1 alterations occurred in 36 of 158 patients with T-cell lymphoma, providing further support for PDCD1 as a clinically relevant putative tumor suppressor. PD-1 expression was increased after oncogenic T-cell signaling in normal T cells, but disruption of the PDCD1 locus blocked this upregulation. In premalignant cells PD-1 increased expression of the tumor suppressor PTEN, thereby reducing signaling by the AKT and PKC kinases to suppress oncogenesis. Conversely, PDCD1 loss allowed rapid development of aggressive lymphomas after oncogenic insult in vivo. Taken together, these findings establish PD-1 as a tumor suppressor in T-cell lymphoma and suggest that checkpoint inhibitors might have the potential to accelerate expansion of oncogenically activated T-cell clones.
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