Review
PD-1 Tumor Suppressor Signaling in T Cell Lymphomas

https://doi.org/10.1016/j.it.2019.03.005Get rights and content

Highlights

T cell lymphomas are aggressive cancers characterized by oncogenic mutations in TCR signaling pathways.

PD-1 is a central tumor suppressor in T cell lymphoma that is frequently inactivated in human T-NHL.

PD-1 activity within malignant human and mouse T cells can negatively regulate the PI3K/AKT and PKCθ/NF-κB tumor survival pathways.

PD-1 targeting checkpoint inhibitors can also accelerate T cell lymphomas under still-undefined conditions.

The inhibitory receptor PD-1 is critical to balancing antigen-induced T cell activation; its inhibition is currently being explored to enhance antitumor T cell immunity with certain successful outcomes. However, PD-1 has also emerged as a central tumor suppressor in T cell lymphomas, where the tumor cell originates from a T cell itself. These aggressive cancers are frequently characterized by oncogenic mutations in T cell receptor (TCR) signaling pathways. PD-1 activity within malignant T cells can negatively regulate the PI3K/AKT and PKCθ/NF-κB tumor survival pathways and PD-1 is frequently inactivated in this human malignancy. This review summarizes current insights into oncogenic T cell signaling, discusses tumor-suppressive functions and mechanisms of PD-1 in T cell lymphomagenesis, and addresses potential unwanted effects caused by PD-1 checkpoint inhibition.

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.

References (121)

  • K. Ishitsuka et al.

    Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma

    Lancet Oncol.

    (2014)
  • A. Broccoli et al.

    Peripheral T-cell lymphoma, not otherwise specified

    Blood

    (2017)
  • L.Y. McGirt

    Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

    Blood

    (2015)
  • D. Vallois

    Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas

    Blood

    (2016)
  • L.A. Pitcher et al.

    T-cell receptor signal transmission: who gives an ITAM?

    Trends Immunol.

    (2003)
  • T.S. Finco

    LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway

    Immunity

    (1998)
  • S.K. Liu

    The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors

    Curr. Biol.

    (1999)
  • P. Rougerie et al.

    Rho GTPases: masters of T lymphocyte migration and activation

    Immunol. Lett.

    (2012)
  • R.L. Boddicker

    Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

    Blood

    (2016)
  • O. Odejide

    A targeted mutational landscape of angioimmunoblastic T-cell lymphoma

    Blood

    (2014)
  • F. Lemonnier

    Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters

    Blood

    (2012)
  • Y.W. Chen

    Receptor-type tyrosine-protein phosphatase kappa directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma

    Blood

    (2015)
  • M.M. Juntilla et al.

    Critical roles of the PI3K/Akt signaling pathway in T cell development

    Immunol. Lett.

    (2008)
  • T. Maehama et al.

    The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate

    J. Biol. Chem.

    (1998)
  • C. Cristofoletti

    Comprehensive analysis of PTEN status in Sezary syndrome

    Blood

    (2013)
  • F. Pages

    Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association

    J. Biol. Chem.

    (1996)
  • G.B. Gmyrek

    Functional analysis of acquired CD28 mutations identified in cutaneous T cell lymphoma

    Cell Immunol.

    (2017)
  • K.A. Sheppard

    PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta

    FEBS Lett.

    (2004)
  • S.M. Horwitz

    Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma

    Blood

    (2018)
  • A. Sors

    Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis

    Blood

    (2006)
  • F. Lemonnier

    New insights in the pathogenesis of T-cell lymphomas

    Curr. Opin. Oncol.

    (2018)
  • E.D. Jacobsen et al.

    Challenges and implications of genomics for T-cell lymphomas

    Hematol. Am. Soc. Hematol. Educ. Program

    (2018)
  • J. Choi

    Genomic landscape of cutaneous T cell lymphoma

    Nat. Genet.

    (2015)
  • L. Wang

    Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes

    Nat. Genet.

    (2015)
  • A.C. da Silva Almeida

    The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome

    Nat. Genet.

    (2015)
  • K. Kataoka

    Integrated molecular analysis of adult T cell leukemia/lymphoma

    Nat. Genet.

    (2015)
  • T. Wartewig

    PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis

    Nature

    (2017)
  • J.M. Vose

    Peripheral T-cell non-Hodgkin’s lymphoma

    Hematol. Oncol. Clin. North Am.

    (2008)
  • S. Park et al.

    Peripheral T cell lymphoma in Asia

    Int. J. Hematol.

    (2014)
  • S.I. Jawed

    Primary cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome): part II. Prognosis, management, and future directions

    J. Am. Acad. Dermatol.

    (2014)
  • S.I. Jawed

    Primary cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome): part I. Diagnosis: clinical and histopathologic features and new molecular and biologic markers

    J. Am. Acad. Dermatol.

    (2014)
  • D.M. Dorfman

    Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma

    Am. J. Surg. Pathol.

    (2006)
  • H.Q. Zhan

    Expression of follicular helper T cell markers in nodal peripheral T cell lymphomas: a tissue microarray analysis of 162 cases

    J. Clin. Pathol.

    (2011)
  • C. Agostinelli

    Peripheral T cell lymphomas with follicular T helper phenotype: a new basket or a distinct entity? Revising Karl Lennert’s personal archive

    Histopathology

    (2011)
  • F.M. Bosisio et al.

    Expression of T-follicular helper markers in sequential biopsies of progressive mycosis fungoides and other primary cutaneous T-cell lymphomas

    Am. J. Dermatopathol.

    (2015)
  • C.Z. Giam et al.

    HTLV-1 infection and adult T-cell leukemia/lymphoma – a tale of two proteins: Tax and HBZ

    Viruses

    (2016)
  • N. Futsch

    HTLV -1, the other pathogenic yet neglected human retrovirus: from transmission to therapeutic treatment

    Viruses

    (2017)
  • C. Agostinelli

    Peripheral T cell lymphoma, not otherwise specified: the stuff of genes, dreams and therapies

    J. Clin. Pathol.

    (2008)
  • J.H. Schatz

    Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis

    Leukemia

    (2015)
  • G. Gaud

    Regulatory mechanisms in T cell receptor signalling

    Nat. Rev. Immunol.

    (2018)

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      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.

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