Bortezomib sensitizes multiple myeloma to NK cells via ER-stress-induced suppression of HLA-E and upregulation of DR5

Carlsten, Mattias; Namazi, Ali; Reger, Robert; Levy, Emily R.; Berg, Maria; Hilaire, Cynthia St.; Childs, Richard W.

doi:10.1080/2162402x.2018.1534664

Cited by 30 publications

(34 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A few studies have reported that endoplasmic reticulum (ER) stress results in posttranscriptional downregulation of surface HLA-E, but not of classical HLA-I levels. It was postulated that this selective loss of HLA-E may be due to HLA-E having a less stable tertiary structure than other classical HLA-I molecules and, thus, a shorter half-life at the plasma membrane (79). So far, few studies have investigated ER stress specifically in HIV-1, but it has been shown that an unfolded-protein response can be detected following in vitro HIV-1 infection of primary PBMCs (80).…”

Section: Discussionmentioning

confidence: 99%

Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

Thans

Akko

Niehrs

et al. 2019

J Virol

View full text Add to dashboard Cite

Human immunodeficiency virus type 1 (HIV-1) has evolved elaborate ways to evade immune cell recognition, including downregulation of classical HLA class I (HLA-I) from the surfaces of infected cells. Recent evidence identified HLA-E, a nonclassical HLA-I, as an important part of the antiviral immune response to HIV-1. Changes in HLA-E surface levels and peptide presentation can prompt both CD8+T-cell and natural killer (NK) cell responses to viral infections. Previous studies reported unchanged or increased HLA-E levels on HIV-1-infected cells. Here, we examined HLA-E surface levels following infection of CD4+T cells with primary HIV-1 strains and observed that a subset downregulated HLA-E. Two primary strains of HIV-1 that induced the strongest reduction in surface HLA-E expression were chosen for further testing. Expression of single Nef or Vpu proteins in a T-cell line, as well as tail swap experiments exchanging the cytoplasmic tail of HLA-A2 with that of HLA-E, demonstrated that Nef modulated HLA-E surface levels and targeted the cytoplasmic tail of HLA-E. Furthermore, infection of primary CD4+T cells with HIV-1 mutants showed that a lack of functional Nef (and Vpu to some extent) impaired HLA-E downmodulation. Taken together, the results of this study demonstrate for the first time that HIV-1 can downregulate HLA-E surface levels on infected primary CD4+T cells, potentially rendering them less vulnerable to CD8+T-cell recognition but at increased risk of NKG2A+NK cell killing.IMPORTANCEFor almost two decades, it was thought that HIV-1 selectively downregulated the highly expressed HLA-I molecules HLA-A and HLA-B from the cell surface in order to evade cytotoxic-T-cell recognition, while leaving HLA-C and HLA-E molecules unaltered. It was stipulated that HIV-1 infection thereby maintained inhibition of NK cells via inhibitory receptors that bind HLA-C and HLA-E. This concept was recently revised when a study showed that primary HIV-1 strains reduce HLA-C surface levels, whereas the cell line-adapted HIV-1 strain NL4-3 lacks this ability. Here, we demonstrate that infection with distinct primary HIV-1 strains results in significant downregulation of surface HLA-E levels. Given the increasing evidence for HLA-E as an important modulator of CD8+T-cell and NKG2A+NK cell functions, this finding has substantial implications for future immunomodulatory approaches aimed at harnessing cytotoxic cellular immunity against HIV.

show abstract

Section: Discussionmentioning

confidence: 99%

Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

Thans

Akko

Niehrs

et al. 2019

J Virol

View full text Add to dashboard Cite

show abstract

“…However, there has been no experimental evidence to date in any preclinical model or human tumor specimens linking either dopamine or dopamine receptors to the immune stimulatory effects of ONC201. Also, ISR activation [45] , [46] , [47] and PI3K/Akt inhibition [48] have been associated with activation of NK cell cytotoxicity and sensitization of tumors cells to NK cells. The relevance of these aspects of the ONC201 mechanism of action for immune activation remains to be evaluated.…”

Section: Onc201 Mechanism Of Actionmentioning

confidence: 99%

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

et al. 2020

View full text Add to dashboard Cite

ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.

show abstract

“…We have examined the clinical effects of ex vivo -expanded autologous NK cells in concert with treatment with the proteasome inhibitor bortezomib (ClinicalTrials.gov: NCT00720785 ), 7 which has been shown to sensitize tumors to NK cell cytotoxicity. 8 , 9 NK cells also contribute to the efficacy observed with monoclonal biologics such as rituximab, as genetic variants of the NK cell receptor CD16, which mediates antibody-dependent cytotoxicity, correlate with anti-tumor responses. 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing ex vivo expansion

Allan

Chakraborty

Waller

et al. 2021

Molecular Therapy - Methods & Clinical Development

Self Cite

View full text Add to dashboard Cite

Transduction of primary human natural killer (NK) cells with lentiviral vectors has historically been challenging. We sought to evaluate multiple parameters to optimize lentiviral transduction of human peripheral blood NK cells being expanded to large numbers using a good manufacturing practice (GMP)-compliant protocol that utilizes irradiated lymphoblastoid (LCL) feeder cells. Although prestimulation of NK cells with interleukin (IL)-2 for 2 or more days facilitated transduction with vesicular stomatitis virus glycoprotein (VSVG)-pseudotyped lentivirus, there was a subsequent impairment in the capacity of transduced NK cells to proliferate when stimulated with LCL feeder cells. In contrast, incubation of human NK cells with LCL feeder cells plus IL-2 before transduction in the presence of the TBK1 inhibitor BX795 resulted in efficient lentiviral integration (mean of 23% transgene + NK cells) and successful subsequent proliferation of the transduced cells. Investigation of multiple internal promoter sequences within the same lentiviral vector revealed differences in percentage and level of transgene expression per NK cell. Bicistronic lentiviral vectors encoding both GFP and proteins suitable for the isolation of transduced cells with magnetic beads led to efficient transgene expression in NK cells. The optimized approaches described herein provide a template for protocols that generate large numbers of fully functional and highly purified lentivirus-transduced NK cells for clinical trials.

show abstract

Bortezomib sensitizes multiple myeloma to NK cells via ER-stress-induced suppression of HLA-E and upregulation of DR5

Cited by 30 publications

References 49 publications

Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing ex vivo expansion

Contact Info

Product

Resources

About