HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM)

Sharifzad, Farzaneh; Mardpour, Soura; Mardpour, Saeid; Fakharian, Esmaeil; Khani, Adeleh Taghi; Sharifzad, Amirhossein; Kiani, Sahar; Heydari, Yasaman; Łos, Marek; Azizi, Zahra; Ghavami, Saeid; Hamidieh, Amir Ali; Ebrahimi, Marzieh

doi:10.3390/ijms21072263

Cited by 34 publications

(30 citation statements)

References 60 publications

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“…The declined cytotoxic function of Hsp70-treated NK cells against K562 and SKOV3 cells in the present study ( Fig. 4), although contrary, can be explained by the dual function of Hsp70 which can also promote the cancer cells viability (Gyrd-Hansen, Nylandsted, & Jaattela, 2004; Multhoff, 2009;Qiao, Liu, & Li, 2008;Sharifzad et al, 2020;Specht et al, 2015;Zorzi & Bonvini, 2011). Furthermore, considering the qRT-PCR results, it can be claimed that treating with Hsp70 led to a reduction in the NK cell lysis capacity compared to the other group.…”

Section: -B-c and 3-a)contrasting

confidence: 53%

Overcoming the UCB HSCs –Derived NK Cells Dysfunctionality through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways

Shokouhifar

Sarab

Yazdanifar

et al. 2020

Preprint

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BackgroundNatural killer (NK) cells differentiated from umbilical cord blood (UCB) hematopoietic stem cells (HSCs) may be more suitable for cell-based immunotherapy compared to NK cells from adult donors. This is due to opportunity to choose alloreactive donors and potentially more robust in vivo expansion. However, the cytotoxicity of UCB-HSC derived NK cells against cancer cells might be suboptimal. To overcome this obstacle, we attempted to generate NK cells with potent antitumor activity by targeting RAS/MAPK, IGF-1R and TGF-β signaling pathways.MethodsThe CD34+ cells isolated from human UCB mononuclear cells through MACS with purity of (≥90%) were used to be differentiated into NK cells. After 21 days of induction with SFTG36, IS721 and IL-15/Hsp70 media, NK cells phenotype was studied and their cytotoxicity against K562 human erythroleukemia cell and SKOV3 ovarian carcinoma cells was analyzed.ResultsThe induced NK cells treated with SFTG36/I721 and SFTG36/IS721 growth factor cocktail expressed a phenotype with CD56+16+CD3- and NKG2D+ with mean fluorescence intensity (MFI) of 92.7%±1.45-168.00±19.20 and 93.23%±0.75-168.66±20.00 respectively. These NK cells once activated by IL-15, demonstrated a higher cytotoxicity against K562 (≥90%) (P ≤ 0.001) and SKOV3 tumor cells (≥65%) (P ≤ 0.001) compared to IL-15/Hsp70 activated NK cells.Conclusion The differentiation of ex vivo-expanded CD34+ cells through manipulation of RAS/MAPK, IGF-1R and TGF-β signaling pathways is an efficient approach for generating functional NK cells that can be used for cancer immunotherapy.

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Section: -B-c and 3-a)contrasting

confidence: 53%

Overcoming the UCB HSCs –Derived NK Cells Dysfunctionality through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways

Shokouhifar

Sarab

Yazdanifar

et al. 2020

Preprint

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“…Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system (CNS) [ 1 , 2 , 3 ]. The tumor is invasive and incurable with poor prognosis and inevitable recurrences [ 4 , 5 ]. The average survival of GBM patients is about 15 months [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Dastghaib

Shojaei

Mostafavi‐Pour

et al. 2020

Cells

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Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva–TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2α inhibitor salubrinal. Simva–TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva–TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2α (eIF2α) phosphorylation, and inhibited autophagic flux (accumulation of LC3β-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva–TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)β-II/LC3β-I ratio in U87 cells, while salubrinal did not affect the Simva–TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva–TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3β-II/LC3β-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva–TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells.

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“…Consequently, the absence of inhibitory signals allows NK cell activation [ 46 , 96 ]. As NK cells have been shown to preferentially kill GSCs [ 97 , 98 ] and penetrate the BBB [ 99 ] in preclinical in vitro and animal models when administered systematically, patients with glioblastoma and high-grade gliomas are now undergoing allogeneic and autologous NK cell administration in clinical trials or are undergoing recruitment (NCT04489420, NCT04254419: ClinicalTrials.gov). To increase natural NK cytotoxicity and attack towards tumors with a heterogeneous expression of CAR target antigens, NK cells can be genetically engineered to express CARs.…”

Section: Immunotherapeutic Strategies For Glioblastomamentioning

confidence: 99%

Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development

Majc

Novak

Kopitar-Jerala

et al. 2021

Cells

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Glioblastoma is the most common brain malignant tumor in the adult population, and immunotherapy is playing an increasingly central role in the treatment of many cancers. Nevertheless, the search for effective immunotherapeutic approaches for glioblastoma patients continues. The goal of immunotherapy is to promote tumor eradication, boost the patient’s innate and adaptive immune responses, and overcome tumor immune resistance. A range of new, promising immunotherapeutic strategies has been applied for glioblastoma, including vaccines, oncolytic viruses, immune checkpoint inhibitors, and adoptive cell transfer. However, the main challenges of immunotherapy for glioblastoma are the intracranial location and heterogeneity of the tumor as well as the unique, immunosuppressive tumor microenvironment. Owing to the lack of appropriate tumor models, there are discrepancies in the efficiency of various immunotherapeutic strategies between preclinical studies (with in vitro and animal models) on the one hand and clinical studies (on humans) on the other hand. In this review, we summarize the glioblastoma characteristics that drive tolerance to immunotherapy, the currently used immunotherapeutic approaches against glioblastoma, and the most suitable tumor models to mimic conditions in glioblastoma patients. These models are improving and can more precisely predict patients’ responses to immunotherapeutic treatments, either alone or in combination with standard treatment.

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HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM)

Cited by 34 publications

References 60 publications

Overcoming the UCB HSCs –Derived NK Cells Dysfunctionality through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways

Overcoming the UCB HSCs –Derived NK Cells Dysfunctionality through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development

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