In T cell non-Hodgkin lymphoma (NHL), oncogenic mutations to the TCR pathway induce chronic proliferation, however, Wartewig et al. found that PD-1 receptor-driven T cell inhibition suppresses oncogenic signaling in premalignant cells. In this context, total or hemizygous knockout of the PD-1 gene led to T cell hyperproliferation and rapid lymphomagenesis; treatment with anti-PD-1 antibodies led to lethal hyperproliferation, but the expanded cells were not lymphomagenic. Caution is warranted in employing checkpoint inhibition in T cell NHL.
T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. 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. 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 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.
Author Info: (1) Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. TranslaTUM, Center for Translational Cancer
Author Info: (1) Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. (2) Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. (3) Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. (4) Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. (5) Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. (6) TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. Department of Medicine II, Klinikum Rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. (7) TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. Department of Medicine II, Klinikum Rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. (8) Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland. (9) Institute of Pathology, Technische Universitat Munchen, 81675 Munchen, Germany. (10) Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. (11) TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Department of Medicine II, Klinikum Rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. (12) Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munchen, Germany. TranslaTUM, Center for Translational Cancer Research, Technische Universitat Munchen, 81675 Munchen, Germany. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. German Center for Infection Research (DZIF), partner site Munich, Germany.
