Trends in Immunology
ReviewPD-1 Tumor Suppressor Signaling in T Cell Lymphomas
Section snippets
Normal and Malignant T Cells
T lymphocytes are key effector cells of the adaptive immune system. They are critical for the elimination of infectious pathogens and the destruction of endogenous cancer cells. However, mature T cells can also transform into cancer cells and develop into malignant lymphomas (called T cell non-Hodgkin lymphoma, T-NHL or peripheral T cell lymphoma, PTCL), which represent particularly aggressive cancers with a still-ill-defined molecular pathogenesis 1, 2, 3. T cells possess clonotypic antigen
T Cell Lymphomas Are a Heterogeneous Group of Malignancies
Mature T cell lymphomas represent a clinical collection of diverse malignancies that, depending on the geographic region, represent 10–30% of all human lymphomas 13, 14. T-NHLs usually have a CD4+ T cell origin and are grouped into several subentities based on their histological and phenotypic characteristics [15]. T-NHLs that primarily infiltrate the skin are referred to as cutaneous T cell lymphomas (CTCLs; see Glossary) and include two major entities, mycosis fungoides (MFs) and Sézary
Oncogenic Activation of TCR Pathways Is a Hallmark of T Cell Lymphomas
Despite the diverse histopathological and clinical presentations of mature T-NHLs and certain subtype-specific pathomechanisms [31], one emerging hallmark of multiple T-NHL entities is the oncogenic activation of signaling pathways that are physiologically engaged by TCRs 7, 8, 9, 10, 11, 32, 33 (Figure 1). This conclusion was based on a series of independent studies performed using whole-genome sequencing, whole-exome sequencing, and mRNA sequencing of primary human T-NHL cases 7, 8, 9, 10, 11
PD-1 Is a Key Tumor Suppressor in T-NHL
To explore the direct consequences of oncogenically promoted T cell pathways in vivo, our laboratory generated a murine model of human T-NHL where the ITK–SYK fusion kinase was conditionally expressed in primary CD4+ T cells (ITK-SYKCD4−creERT2 mice) [12]. While the expression of ITK–SYK only in mature CD4+ T cells could trigger their massive expansion, this response was only transient and insufficient to drive cancer [12]. A subsequent unbiased in vivo mutagenesis screen uncovered transposon
Putative Tumor-Suppressor Mechanisms of PD-1
The tumor-suppressive mechanisms of PD-1 signaling remain largely unclear. Yet, it is conceivable that these might overlap with the physiological pathways involved in PD-1 signaling, which restrict antigen-induced TCR responses at tolerance checkpoints, and which may also serve to prevent autoimmunity and immunopathology (Figure 2, Key Figure). It is well established that under physiological conditions, PD-1 protein expression is upregulated on the cell surface of activated T cells, and PD-1
PD-1 Checkpoint Inhibition in T Cell Lymphoma
The PD-1 checkpoint pathway is currently receiving a lot of attention in immuno-oncology because it can trigger exhaustion and dysfunctionality in CD8+ T cells directed against cancer cells in suppressive tumor microenvironments 90, 91, 92, 93. Consequently, antibody-mediated checkpoint inhibition targeting either the PD-1 receptor [nivolumab (BMS, 2014), pembrolizumab (Merck, 2014)], or its ligand, PD-L1 [atezolizumab (Roche, 2016), avelumab (Merck Serono and Pfizer, 2017) and durvalumab
Concluding Remarks
The past decade has seen significant progress in our understanding of PD-1 functions. In addition to the prevention of immunopathology after chronic antigenic stimulation, this unique receptor has evolved as an important tumor suppressor in the T cell lineage, counteracting oncogenic signals mediated via the PI3K/AKT and PKCθ/NF-κB pathways [12]. These insights provide new routes for exploring the poorly understood pathogenesis of T cell lymphomas and indicate that inhibiting PI3K signaling
Acknowledgments
Work in the authors’ laboratory is supported by research grants from the DFG, the German Research Foundation (SFB 1054/B01, project number 360372040–SFB 1335/P01 and P08, TRR 237/A10, and RU 695/9-1), and the ERC (FP7, grant agreement No. 322865) to J.R. The authors thank Lara Hartjes for help with the figures.
Glossary
- Adult T cell leukemia/lymphoma (ATLL)
- neoplasm of mature T cells etiologically linked to HTLV-1. Disease manifestations are subcategorized depending on their clinical course: acute, chronic, smoldering, lymphoma.
- Anaplastic large cell lymphoma (ALCL)
- distinguished from other lymphomas by their anaplastic cytology and constant surface expression of CD30.
- Angioimmunoblastic T cell lymphoma (AITL)
- characterized by generalized lymphadenopathy, high fever, skin rash, and autoimmune-like manifestations.
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2022, GeneCitation Excerpt :Molecular function (MF) of GO analysis demonstrated that these DEIRGs were most involved in receptor ligand activity, signaling receptor activator activity and growth factor activity, which were closely related to immune response (Kang et al., 2021) (Fig. 3A). KEGG analysis showed signaling pathways of these DEIRGs such as MAPK signaling pathway, IL-7 signaling pathway and PI3K-Akt signaling pathway, which were reported to play vital roles in tumors and tumor immunity by several articles (Kobayashi et al., 2020; Zhao et al., 2020; Wartewig and Ruland, 2019) (Fig. 3B). Protein-protein interaction (PPI) network based on Metascape database showed that these genes were clustered in 16 MCODE components (Fig. 3C).
Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity
2021, BloodCitation Excerpt :Compared with wild-type controls, ITK-SYK expressing murine CD4+ T cells have upregulated expression of exhaustion markers found in human PD1 wild-type CTCLs, such as Pdcd1, Tigit, and Lag3 (Figure 6A). To determine the functional effects of PD1 deletions, we then generated isogenic pairs of ITK-SYK–expressing cells, with or without deletions of the PD1 locus14,37 (Figure 6B). This model incorporates an inducible Cre recombinase.
Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade
2019, BloodCitation Excerpt :Similar mutations were described as activating mutations in 15% to 30% of ATLL cases, resulting in increased stability of the Notch1 protein and enhanced proliferation of ATLL cells.8,38-40 PD-1 was identified as a potent tumor suppressor in the context of a T-cell malignancy driven by constitutive TCR signaling, and its inhibition is hypothesized to increase costimulatory CD28 signaling and the downstream phosphatidylinositol 3-kinase/AKT pathway.41,42 However, expression of PTEN, PRKCQ, and AKT1 remained unaffected by nivolumab treatment in patients 1 and 3.