Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy

Sánchez-Correa, Beatriz; López-Sejas, Nelson; Durán, Esther; Labella, Fernando; Alonso, Corona; Solana, Rafael; Tarazona, Raquel

doi:10.1007/s00262-019-02336-6

Cited by 45 publications

(38 citation statements)

References 53 publications

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“…Finally, etigilimab inhibited the growth of patient‐derived melanoma in mice reconstituted with human haematopoietic stem cells . Etigilimab was tested for its safety and pharmacokinetics in a Phase I, dose‐escalation study (NCT031119428) as a single agent or in combination with nivolumab (anti‐PD‐1 mAb) to treat various advanced or metastatic solid malignancies . In spite of the success of the Phase Ia trial and etigilimab being well tolerated at doses up to 20 mg/kg, the Phase Ib clinical trial was terminated due to sponsor decision.…”

Section: Translating Tigit Blockade Into the Clinicsmentioning

confidence: 99%

TIGIT as an emerging immune checkpoint

Harjunpää

Guillerey

2019

Clinical and Experimental Immunology

340

311

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T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging target in cancer immunotherapy. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumour cells to downregulate T cell and natural killer (NK) cell functions. TIGIT has emerged as a key inhibitor of anti-tumour responses that can hinder multiple steps of the cancer immunity cycle. Pre-clinical studies indicated that TIGIT blockade may protect against various solid and haematological cancers. Several monoclonal antibodies (mAbs) that block the inhibitory activity of human TIGIT have been developed. Clinical trials are ongoing, investigating TIGIT blockade as a monotherapy or in combination with anti-PD1/PD-L1 mAbs for the treatment of patients with advanced solid malignancies. In this review, we cover our current knowledge on TIGIT, from its discovery in 2009 to its current status as a clinical target.

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Section: Translating Tigit Blockade Into the Clinicsmentioning

confidence: 99%

TIGIT as an emerging immune checkpoint

Harjunpää

Guillerey

2019

Clinical and Experimental Immunology

340

311

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“…In recent years, the field of immunotherapy has emerged as one of the most promising approaches for treating cancer (1). Though most immunotherapies have traditionally focused on T-cells, NK cell-based therapies are rapidly emerging in research and in the clinic (2,3).…”

Section: Introduction Nk Cells and Cancermentioning

confidence: 99%

“…Various approaches have been developed to bolster NK cell activity against cancer, some of which are being utilized in pre-clinical and clinical trials (3,14). Significant hurdles still persist, however, for immunotherapeutic treatments in general, and for NK cells in particular.…”

Section: Introduction Nk Cells and Cancermentioning

confidence: 99%

“…Recent comprehensive reviews provide detailed descriptions and delineate the obstacles remaining in multiple NK-based treatments that have been developed and tested in preclinical and clinical trials. These reviews cover topics including cytokine therapy, hematopoietic stem cell transplantation (HSCT), adoptive cell transfer, and CAR-NK therapy (2,3,(22)(23)(24)(25). Here, we summarize recent pre-clinical and clinical evidence regarding NK cell expression of checkpoint molecules and some of the most recent NK-based immunotherapeutic strategies.…”

Section: Introduction Nk Cells and Cancermentioning

confidence: 99%

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Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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“…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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Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy

Cited by 45 publications

References 53 publications

TIGIT as an emerging immune checkpoint

TIGIT as an emerging immune checkpoint

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

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

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