PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis

Loss of the PD-1 receptor promotes the development of T cell non-Hodgkin lymphomas by modulating oncogenic signalling pathways, and blocking these pathways reduces tumourigenesis. Checkpoint factor suppresses lymphoma PD-1 functions as an inhibitory receptor in the immune system and is a target of cancer immunotherapy. Jürgen Ruland and colleagues now show that PD-1 also functions as a tumour suppressor that is often lost in human T cell lymphomas. Experimentally, loss of PD-1 promotes the development of T cell non-Hodgkin lymphomas by modulating oncogenic signalling pathways. Blocking these pathways reduces tumorigenesis. These findings may have implications for T cell lymphoma therapies. T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes 1 . T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules 1 , 2 , 3 , 4 . Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo . However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1 , which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological funct