Engineered human pluripotent stem cell-derived natural killer cells with PD-L1 responsive immunological memory for enhanced immunotherapeutic efficacy

Chang, Yun; Jin, Gyuhyung; Luo, Weichuan; Luo, Qian; Jung, Juhyung; Hummel, Sydney N.; Torregrosa-Allen, Sandra; Elzey, Bennett D.; Low, Philip S.; Lian, Xiaojun; Bao, Xiaoping

doi:10.1016/j.bioactmat.2023.03.018

Cited by 8 publications

(4 citation statements)

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“…41,42 Synthetic receptors that can respond to interior inflammation signals could be used on the artificial cells, which may avoid such risks. 43 Continued research and development efforts should focus on advancing the understanding of artificial cells and their functionalities. 2,3,6 This includes exploring new materials, improving fabrication techniques, and enhancing the integration of top-down and bottom-up approaches.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Irradiated K562/HL60 cells or patient-derived nontumor cells may be a better cell source for clinical artificial cell engineering. Second, long-term surviving neutrophils or an excessive neutrophil count may cause neutrophilia. , Thus, artificial neutrophils should be engineered with a drug-responsive suicide gene or other safety switches to avoid such risks. , Third, CNO used in this study to activate the hM4Di receptors on artificial neutrophils may be reverse-metabolized to bioactivate clozapine and exert clozapine-mediated effects. , Synthetic receptors that can respond to interior inflammation signals could be used on the artificial cells, which may avoid such risks …”

Section: Discussionmentioning

confidence: 99%

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Engineered Artificial Human Neutrophils Exhibit Mature Functional Performance

Chang,

Hummel,

Watson

et al. 2023

ACS Synth. Biol.

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Neutrophils, a key innate immune component, are powerful effector leukocytes for mediating opposing effects on tumor progression and ameliorating pathogen infections. However, their short lifespan and complex purification process have limited neutrophil clinical applications. Here we combined genetic engineering technology with a nanodrug system to construct artificial neutrophils that display functions similar to those of native neutrophils. K562 and HL60 human leukemia cells were engineered to express the human G protein-coupled receptor hM4Di. Compared to the parental cells, engineered hM4Di-K562 and hM4Di-HL60 cells exhibited excellent chemotaxis ability towards clozapine-N-oxide (CNO) and superior bacteria phagocytic behavior, resembling native neutrophils. The antibacterial ability of the hM4Di-K562 cells was further enhanced by loading them with the glycopeptide vancomycin via mesoporous silica nanoparticles (Nano@Van). Our proposed artificial cell engineering platform provides a new avenue to investigate the physiological properties of neutrophils.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Engineered Artificial Human Neutrophils Exhibit Mature Functional Performance

Chang,

Hummel,

Watson

et al. 2023

ACS Synth. Biol.

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“…A low absolute lymphocyte count in peripheral blood predicts poor survival in DLBCL treated with R-CHOP, particularly in the non-germinal center B cell-like (non-GCB) type [ 5 – 8 ]. As a subtype of lymphocyte, natural killer (NK) cell is the first line of defense that shows a strong function in tumor immunotherapy response and clinical outcomes [ 9 ]. Lee et al have suggested NK cell count before R-CHOP therapy as a potential prognostic factor in de novo DLBCL patients [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Prognostic impact of absolute peripheral blood NK cell count after four cycles of R-CHOP-like regimen treatment in patients with diffuse large B cell lymphoma

Huo,

Chen,

Zhao

et al. 2023

Clin Exp Med

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As a subtype of lymphocyte, natural killer (NK) cell is the first line of defense that shows a strong function in tumor immunotherapy response and clinical outcomes. The current study aims to investigate the prognostic influence of peripheral blood absolute NK cell count after four cycles of rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) treatment (NKCC4) in diffuse large B cell lymphoma (DLBCL) patients. A total of 261 DLBCL patients treated with R-CHOP from January 2018 to September 2022 were enrolled. The low NKCC4 was observed in patients who died during the study period compared with survival individuals. A NKCC4 < 135 cells/μl had a remarkable negative influence in overall survival and progression-free survival (PFS) compared to a NKCC4 ≥ 135 cells/μl (p < 0.0001 and p < 0.0004, respectively). In addition, the OS and PFS were synergistically lower in a NKCC4 < 135 cells/μl group among DLBCL patients with GCB type or high IPI. In conclusion, this study indicates NCKK4 as a valuable marker in clinical practice and provides an insight for combination treatment of R-CHOP to improve outcomes of DLBCL patients.

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“…Despite multiple conventional therapy, including surgical resection, chemoradiotherapy and immunotherapy, glioma still possess a high recurrence and fatality rate ( Dong et al, 2023 ). The impact of immunotherapy on glioma has become one of the hottest areas of research owing to its effectiveness in treating various solid tumors and hematological cancers in recent years ( Chang et al, 2023 ; Hovhannisyan et al, 2023 ). The advancement of genomics has led to the identification of some molecular markers associated with specific gliomas phenotypes such as isocitrate dehydrogenase (IDH) ( Nuechterlein et al, 2021 ), phosphoinositide 3-kinase (PI3K) ( Yan et al, 2020 ), telomerase reverse transcriptase (TERT) ( Park et al, 2022 ), and phosphatase and tensin homolog (PTEN) ( Cheng et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Ceruloplasmin is associated with the infiltration of immune cells and acts as a prognostic biomarker in patients suffering from glioma

et al. 2023

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Glioma is regarded as a prevalent form of cancer that affects the Central Nervous System (CNS), with an aggressive growth pattern and a low clinical cure rate. Despite the advancement of the treatment strategy of surgical resection, chemoradiotherapy and immunotherapy in the last decade, the clinical outcome is still grim, which is ascribed to the low immunogenicity and tumor microenvironment (TME) of glioma. The multifunctional molecule, called ceruloplasmin (CP) is involved in iron metabolism. Its expression pattern, prognostic significance, and association with the immune cells in gliomas have not been thoroughly investigated. Studies using a variety of databases, including Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gliovis, showed that the mRNA and protein expression levels of CP in patients suffering from glioma increased significantly with an increasing glioma grade. Kaplan-Meier (KM) curves and statistical tests highlighted a significant reduction in survival time of patients with elevated CP expression levels. According to Cox regression analysis, CP can be utilized as a stand-alone predictive biomarker in patients suffering from glioma. A significant association between CP expression and numerous immune-related pathways was found after analyzing the data using the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Tumor Immune Estimation Resource (TIMER) and CIBERSORT analyses indicated a substantial correlation between the CP expression and infiltration of immunocytes in the TME. Additionally, immune checkpoints and CP expression in gliomas showed a favorable correlation. According to these results, patients with glioma have better prognoses and levels of tumor immune cell infiltration when their CP expression is low. As a result, CP could be used as a probable therapeutic target for gliomas and potentially anticipate the effectiveness of immunotherapy.

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Engineered human pluripotent stem cell-derived natural killer cells with PD-L1 responsive immunological memory for enhanced immunotherapeutic efficacy

Cited by 8 publications

References 70 publications

Engineered Artificial Human Neutrophils Exhibit Mature Functional Performance

Engineered Artificial Human Neutrophils Exhibit Mature Functional Performance

Prognostic impact of absolute peripheral blood NK cell count after four cycles of R-CHOP-like regimen treatment in patients with diffuse large B cell lymphoma

Ceruloplasmin is associated with the infiltration of immune cells and acts as a prognostic biomarker in patients suffering from glioma

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