PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis

Abstract

T cell non-Hodgkin lymphomas (T-NHLs) represent a heterogeneous group of highly aggressive malignancies with poor clinical outcomes1. T-NHLs originate from peripheral T lymphocytes and are frequently characterized by genetic gain-of-function variants in T cell antigen receptor (TCR) signalling molecules1–4. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and survival programmes, it remains unclear whether T cells harbour tumour suppressors that can counteract these events. Using a murine model of human T cell lymphoma, we demonstrate that the acute enforcement of oncogenic TCR signalling in lymphocytes 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 suppressing oncogenic T cell signalling. Mono- and bi-allelic PDCD1 deletions are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, PD-1 activity enhances PTEN levels and attenuates AKT and PKC signalling in pre-malignant cells. In 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. Altogether, these results indicate that the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T-NHLs that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.

Programming CAR-T cells to kill cancer

“…However, caution must be exercised with such approaches as these inhibitory receptors are part of physiological processes involved in modulating T-cell activity, and permanently unleashing T cells with no feedback and attenuation mechanisms may increase the risk of toxicity owing to uncontrolled activation. Importantly, recent work demonstrated that PD-1 is a tumour suppressor gene, raising the possibility that deletion of PD-1 in engineered T cells could ultimately increase the risk of malignant transformation 157 .…”

Novel Immunotherapies for T Cell Lymphoma and Leukemia

“…PD-1 blockade in these models seems to promote PI3K/AKT activity and tumor growth. PI3K/AKT is the target of PI3K-inhibitors like duvelisib, that have recently demonstrated good activity in TCL (43, 44). It seems evident that the use of checkpoint inhibitors in TCL with oncogenically activated TCR pathways needs to be preceded by some special considerations(43).…”

The dark side of PD-1 receptor inhibition

“…As such, anti-PD-1 treatment triggers an immune response, b , Wartewig et al . 1 have demonstrated that PD-1 signalling in a mouse model of T cell non-Hodgkin’s lymphoma prevents proliferation of cancerous T cells (the source of the PD-1 ligand was not defined). In these mice, anti-PD-1 treatment can aggravate disease by reactivating the cancerous cells to enable their continuous proliferation.…”

“…Wartewig et al . 1 report on page 121 that a widely used cancer immunotherapy actively promotes tumour progression in a mouse model of a cancer called T-cell non-Hodgkin’s lymphoma (T-NHL).…”