TIGIT and PD-1 Mark Intratumoral T Cells with Reduced Effector Function in B-cell Non-Hodgkin Lymphoma

Josefsson, Sarah E.; Beiske, Klaus; Blaker, Yngvild Nuvin; Førsund, Mette; Holte, Harald; Østenstad, Bjørn; Kimby, Eva; Köksal, Hakan; Wälchli, Sébastien; Bai, Baoyan; Smeland, Erlend B.; Levy, Ronald; Kolstad, Arne; Huse, Kanutte; Myklebust, June Helen

doi:10.1158/2326-6066.cir-18-0351

Cited by 94 publications

(93 citation statements)

References 31 publications

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“…Clinically, the presence and ongoing inhibitory effect of other immune checkpoint molecules may explain the lack of benefit of anti-PD-1/PD-L1 monotherapy in CLL [53,54]. In CLL, some of these additional immune checkpoints such as T-cell immunoglobulin domain and mucin domain protein 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), or T-cell immunoreceptor with Ig and ITIM domains (TIGIT) are coexpressed by PD-1 + T cells [55,56].…”

Section: T-cell Functionmentioning

confidence: 99%

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Mhibik¹,

Wiestner²,

Sun³

2019

IJMS

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B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.

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Section: T-cell Functionmentioning

confidence: 99%

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Mhibik¹,

Wiestner²,

Sun³

2019

IJMS

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“…TIGIT is an inhibitory receptor that has been associated with hypofunctional/exhausted NK cells in cancer patients and mouse models of solid tumors [31,35] and with exhausted CD8 + T cells in hematologic malignancy and in HIV infection [36,39,43]. As a result, several studies have explored the use of TIGIT blockade to rescue T and NK cell function.…”

Section: Nk Cells Undergo Significant Changes During Chronic Hiv Infementioning

confidence: 99%

“…The TIGIT inhibitory signal is mediated by ligation with its high affinity ligand, the poliovirus receptor (CD155 or PVR), and its low affinity ligand CD112 (Nectin-2 or PVRL2) [30,32,33]. TIGIT has been previously associated with CD4 + T cell, CD8 + T cell and NK cell exhaustion both in the setting of chronic viral infections and malignancy [31,[34][35][36][37][38][39][40]. Blockade of the TIGIT/CD155/CD112 pathway to improve the function of T cells and NK cells against solid cancers is currently under investigation [41,42].…”

Section: Introductionmentioning

confidence: 99%

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Vendrame

Seiler

Ranganath

et al. 2019

Preprint

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Objective: Our objective was to investigate the mechanisms that govern natural killer (NK) cell responses to HIV, with a focus on specific receptor-ligand interactions involved in HIV recognition by NK cells. Design and Methods: We first performed a mass cytometry-based screen of NK cell receptor expression patterns in healthy controls and HIV + individuals. We then focused mechanistic studies on the expression and function of T cell immunoreceptor with Ig and ITIM domains (TIGIT). Results: The mass cytometry screen revealed that TIGIT is upregulated on NK cells of untreated HIV + women, but not in antiretroviral-treated women. TIGIT is an inhibitory receptor that is thought to mark exhausted NK cells; however, blocking TIGIT did not improve anti-HIV NK cell responses. In fact, the TIGIT ligands CD112 and CD155 were not upregulated on CD4 + T cells in vitro or in vivo, providing an explanation for the lack of benefit from TIGIT blockade. TIGIT expression marked a unique subset of NK cells that express significantly higher levels of NK cell activating receptors (DNAM-1, NTB-A, 2B4, CD2) and exhibit a mature/adaptive phenotype (CD57 hi , NKG2C hi , LILRB1 hi , FcRγ lo , Syk lo ). Furthermore, TIGIT + NK cells had increased responses to mock-infected and HIV-infected autologous CD4 + T cells, and to PMA/ionomycin, cytokine stimulation and the K562 cancer cell line. Conclusions: TIGIT expression is increased on NK cells from untreated HIV + individuals. Although TIGIT does not participate directly in NK cell recognition of HIV, it marks a population of mature/adaptive NK cells with increased functional responses. Antibody conjugation, mass cytometry staining and data acquisitionAntibodies were conjugated using MaxPar® ×8 labeling kits (Fluidigm). To ensure antibody stability over time, antibody panels were lyophilized into single-use pellets prior to use (Biolyph). Cells were stained for mass cytometry as described previously [51,52] and resuspended in 1× EQ Beads (Fluidigm) before acquisition on a Helios mass cytometer (Fluidigm). In vitro HIV infectionReplication competent (Q23-FL) HIV-1 was made by transfection and titrated as described [51]. CD4 + T cells were activated for 2 days with plate-bound anti-CD3 (clone OKT3, eBioscience, 10 µg/ml), soluble anti-CD28/CD49d (clones L293/L25, BD Biosciences, 1 µg/ml each) and phytohemagglutinin (eBioscience, 2.5 µg/ml). CD4 + T cells were infected overnight with Q23-FL via ViroMag R/L magnetofection (Oz Biosciences) at a multiplicity of infection of 20. HIV infection was as measured by intracellular p24. TIGIT blockade assayCells were cultured in RPMI media containing 10% FBS (Thermo Fisher Scientific) and 1% penicillin/streptomycin/amphotericin (Thermo Fisher Scientific) (RP10). NK cells were incubated in 24-well plates at a concentration of 2x10 6 cells/ml in for 3 days at 37°C with 5% CO2, with addition of rhIL-2 (R&D Systems, 300 IU/ml). After 3 days, NK cells were washed with fresh media and plated in 96-well plates (80,000-100,000 cells/well). Blocking mIgG1κ anti-h...

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“…Approximately 78-83% of CD8 + and 69-70% of CD4 + T effector memory cells (TEMs) are simultaneously positive for these two inhibitory molecules, and these TEMs have limited capability for IL-2, IFN-γ, and TNF-α secretion. 413 In FL, TIGIT is mainly expressed by CD8 + effector and memory T cells and is related to advanced disease stage. 414 TIM-3 inhibits Th1 cell responses, 415 and its antibodies have been found to potently enhance antitumor immunity.…”

Section: Tumor Microenvironment and Checkpoint-related Targeted Therapymentioning

confidence: 99%

Advances in targeted therapy for malignant lymphoma

Wang

Qin

Huo

et al. 2020

Sig Transduct Target Ther

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The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors, immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment. Although these targeted agents have shown great success in treating lymphoma patients, adverse events should be noted. The selection of the most suitable candidates, optimal dosage, and effective combinations warrant further investigation. In this review, we systematically outlined the advances in targeted therapy for malignant lymphoma, providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.Signal Transduction and Targeted Therapy (2020) 5:15; https://doi.

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TIGIT and PD-1 Mark Intratumoral T Cells with Reduced Effector Function in B-cell Non-Hodgkin Lymphoma

Cited by 94 publications

References 31 publications

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Advances in targeted therapy for malignant lymphoma

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