PD-L2 is expressed on activated human T cells and regulates their function

Messal, Nassima; Serriari, Nacer-Eddine; Pastor, Sonia; Nunès, Jacques A.; Olive, Daniel

doi:10.1016/j.molimm.2011.06.436

Cited by 100 publications

(78 citation statements)

References 24 publications

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“…It is noteworthy that PD-L2 function has not been fully characterized, and we showed for the first time that PD-L2 delivers intrinsic signals that negatively regulate human T-cell function. After our initial submission of this manuscript, Messal et al 25 recently reported that PD-L2 is expressed on activated human T cells and regulates their function, which is consistent with our results. However, all these studies, including our own, did not explore the signaling events of PD-L1 and PD-L2.…”

Section: Discussionsupporting

confidence: 91%

siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T-cell effector functions

et al. 2011

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Adoptive cell therapy using tumor-specific T cells is a promising strategy for treating patients with malignancy. However, accumulating evidences have demonstrated that optimal function of tumor-reactive T cells is often attenuated by negative regulatory signal(s) delivered through receptors, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and their cognate ligands. Although systemic blocking of these molecules needs careful attention on the risk of uncontrolled immune activation, selective inhibition of negative signals in tumor-specific T cells by their genetic modification is an attractive approach to overcome immunological suppression in cancer patients. Here, we demonstrate the improved effector functions of tumor-specific CD4(+) and CD8(+) human T cells by small interfering RNA (siRNA) -mediated silencing of PD-1 ligands, PD-L1 or PD-L2. Tumor antigen MAGE-A4-specific human T-cell clones upregulated the expression of PD-1 ligands upon activation. siRNA-mediated knockdown of PD-L1 or -L2 enhanced the interferon-γ production and antigen-specific cytotoxicity of these cells. Peripheral blood mononuclear cells transduced with a retroviral vector encoding MAGE-A4-specific T-cell receptor α/β chains also increased their effector functions by this modification. These results suggest that siRNA-mediated knockdown of PD-1 ligands is an attractive strategy to inhibit a negative regulatory mechanism of tumor-specific T cells resulting in enhanced efficacy of adoptive T-cell therapy of cancer using genetically modified autologous lymphocytes.

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Section: Discussionsupporting

confidence: 91%

siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T-cell effector functions

et al. 2011

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“…40 In addition to downstream signaling of PD-L1, 41 also engagement of PD-L2 resulted in T-cell inhibition, further illustrating the complexity of these interactions. 42 It has been well demonstrated that PD-1 plays a crucial role in T-cell regulation in various immune responses, such as peripheral tolerance, autoimmunity, infection, and antitumor immunity. 36 Elevated PD-1 expression on viral antigen-specific CD8 ϩ T cells in chronic viral infections was recognized as a hallmark for T-cell dysfunction on antigen restimulation.…”

Section: Pd-1mentioning

confidence: 99%

Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention

Norde

Hobo

Voort

et al. 2012

Blood

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The adaptive immune system can be a potent defense mechanism against cancer; however, it is often hampered by immune suppressive mechanisms in the tumor microenvironment. Coinhibitory molecules expressed by tumor cells, immune cells, and stromal cells in the tumor milieu can dominantly attenuate T-cell responses against cancer cells. Today, a variety of coinhibitory molecules, including cytotoxic T lymphocyte-associated antigen-4, programmed death-1, B and T lymphocyte attenuator, LAG3, T-cell immunoglobulin and mucin domain 3, and CD200 receptor, have been implicated in immune escape of cancer cells. Sustained signaling via these coinhibitory molecules results in functional exhaustion of T cells, during which the ability to proliferate, secrete cytokines, and mediate lysis of tumor cells is sequentially lost. In this review, we discuss the influence of coinhibitory pathways in suppressing autologous and allogeneic T cell-mediated immunity against hematologic malignancies. In addition, promising preclinical and clinical data of immunotherapeutic approaches interfering with negative cosignaling, either as monotherapy or in conjunction with vaccination strategies, are reviewed. Numerous studies indicate that coinhibitory signaling hampers the clinical benefit of current immunotherapies. Therefore, manipulation of coinhibitory networks is an attractive adjuvant immunotherapeutic intervention for hematologic cancers after standard treatment with chemotherapy and hematopoietic stem cell transplantation. (Blood. 2012;120(4): 728-736) IntroductionDespite the powerful aspects of immune reactions, most often tumor cells are able to evade immune recognition and destruction. Mechanisms exploited by tumor cells to escape T cell-mediated immunity include disruption of antigen presentation, downregulation of HLA molecules, secretion of immune suppressive cytokines, as well as recruitment of regulatory T cells (T REG ) and myeloid-derived suppressor cells. 1 In the last decade, another powerful immune suppressive mechanism gained much attention: the repressive action of coinhibitory molecules. 2 Activation of T cells is predominantly dependent on both costimulatory and coinhibitory members, including members of the B7/ CD28 family. The balance between positive and negative cosignals determines the functionality of T cells during immunity and tolerance. In addition to the native role of cosignaling, tumor cells can evade immune control by down-regulating costimulatory molecules, such as CD80 and CD86, and up-regulating various coinhibitory ligands, thereby limiting the therapeutic potential of current immunotherapy against cancer.Standard treatment for hematologic cancers includes chemotherapy and radiotherapy, which reduce tumor burden and can induce long-term remission. Moreover, in the past years, new therapeutics, including imatinib, dasatinib, rituximab, bortezomib, and lenalidomide, have been developed that target tumor cells. However, drug resistance and relapse remain major problems. In addition, cellular immunotherapy ...

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“…Several human malignancies upregulate PD-L1, and this has been shown to correlate inversely with survival in many types of cancer (8)(9)(10)(11)(12)(13). The expression of PD-L2 was believed to be much more restricted and limited to the surface of activated dendritic cells and macrophages (14), although recently its expression was shown in activated human T cells and various tumor cells (15,16).…”

mentioning

confidence: 99%

B7-DC-Ig Enhances Vaccine Effect by a Novel Mechanism Dependent on PD-1 Expression Level on T Cell Subsets

Mkrtichyan

Najjar

Raulfs

et al. 2012

The Journal of Immunology

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Programmed death receptor 1 (PD-1) is an important signaling molecule often involved in tumor-mediated suppression of activated immune cells. Binding of this receptor to its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), attenuates T cell activation, reduces IL-2 and IFN-γ secretion, decreases proliferation and cytotoxicity, and induces apoptosis. B7-DC-Ig is a recombinant protein that binds and targets PD-1. It is composed of an extracellular domain of murine B7-DC fused to the Fc portion of murine IgG2a. In this study, we demonstrate that B7-DC-Ig can enhance the therapeutic efficacy of vaccine when combined with cyclophosphamide. We show that this combination significantly enhances Ag-specific immune responses and leads to complete eradication of established tumors in 60% of mice and that this effect is CD8 dependent. We identified a novel mechanism by which B7-DC-Ig exerts its therapeutic effect that is distinctly different from direct blocking of the PD-L1–PD-1 interaction. In this study, we demonstrate that there are significant differences between levels and timing of surface PD-1 expression on different T cell subsets. We found that these differences play critical roles in anti-tumor immune effect exhibited by B7-DC-Ig through inhibiting proliferation of PD-1high CD4 T cells, leading to a significant decrease in the level of these cells, which are enriched for regulatory T cells, within the tumor. In addition, it also leads to a decrease in PD-1high CD8 T cells, tipping the balance toward nonexhausted functional PD-1low CD8 T cells. We believe that the PD-1 expression level on T cells is a crucial factor that needs to be considered when designing PD-1–targeting immune therapies.

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PD-L2 is expressed on activated human T cells and regulates their function

Cited by 100 publications

References 24 publications

siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T-cell effector functions

siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T-cell effector functions

Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention

B7-DC-Ig Enhances Vaccine Effect by a Novel Mechanism Dependent on PD-1 Expression Level on T Cell Subsets

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