Targeting Natural Killer T Cells in Solid Malignancies

Ingram, Zewde; Madan, Shriya; Merchant, Jenoy; Carter, Zakiya; Gordon, Zen; Carey, Gregory B.; Webb, Tonya J.

doi:10.3390/cells10061329

Cited by 16 publications

(11 citation statements)

References 96 publications

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“…Moreover, NKT-like cells expressing prominent functional receptors NKp30, NKp46, and CD161 were reduced, whereas KIR2DL2/L3/S3+NKT-like cells were increased in the PF. It is also reported that NKT-like cells participate directly or indirectly in anti-tumor immunity [27]. Similar to NK cells, NKT-like cell activation depends on the balance between the stimulatory and inhibitory signals generated by the engagement of NCRs and KIRs to their cognate ligands [27].…”

Section: Discussionmentioning

confidence: 99%

“…It is also reported that NKT-like cells participate directly or indirectly in anti-tumor immunity [27]. Similar to NK cells, NKT-like cell activation depends on the balance between the stimulatory and inhibitory signals generated by the engagement of NCRs and KIRs to their cognate ligands [27]. Thus, dysregulated receptor expression on tumor-associated NKT-like cells may impair their anti-tumor response.…”

Section: Discussionmentioning

confidence: 99%

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Immune Profile of Blood, Tissue and Peritoneal Fluid: A Comparative Study in High Grade Serous Epithelial Ovarian Cancer Patients at Interval Debulking Surgery

et al. 2022

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High-grade serous epithelial ovarian carcinoma (HGSOC) is an immunogenic tumor with a unique tumor microenvironment (TME) that extends to the peritoneal cavity. The immunosuppressive nature of TME imposes the major challenge to develop effective treatment options for HGSOC. Interaction of immune cells in TME is an important factor. Hence, a better understanding of immune profile of TME may be required for exploring alternative treatment options. Immune profiling of peritoneal fluid (PF), tumor specimens, and blood were carried out using flowcytometry, ELISA, and Procartaplex immunoassay. The frequency of CD56BrightNK cells and expression of functional receptors were reduced in PF. Increased activating NKp46+CD56DimNK cells may indicate differential antitumor response in PF. Functional receptors on NK, NKT-like and T cells were reduced more drastically in tumor specimens. Soluble ligands MIC-B and PVR were reduced, whereas B7-H6 was increased in PF. Dissemination of tumor cells contributes to soluble ligands in PF. A differential cytokine profile was found in serum and PF as IL-2, IL-8, IL-15, IL-27, IFN-γ, and GM-CSF were elevated specifically in PF. In conclusion, the differential immune profile and correlation of soluble parameters and NK cell receptors with chemo response score may add knowledge to understand anti-tumor immune response to develop effective treatment modality.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immune Profile of Blood, Tissue and Peritoneal Fluid: A Comparative Study in High Grade Serous Epithelial Ovarian Cancer Patients at Interval Debulking Surgery

et al. 2022

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“…Indeed, there is an increasing investigation in establishing an effective immune cell-based therapy for GC by ex vivo activating and expanding immune cells. Multifarious studies have presented the therapeutic potential of effective immunotherapy of immune cells ( Rezvani, Daher et al, 2020 ; Ingram, Madan et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Adaptive NK Cell Therapy Modulated by Anti-PD-1 Antibody in Gastric Cancer Model

et al. 2021

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Recently, adaptive NK cell therapy has become a promising treatment but has limited efficacy as a monotherapy. The identification of immune checkpoint inhibitor (ICI) molecules has opened a new horizon of immunotherapy. Herein, we aimed to demonstrate the cytotoxic effects of a polytherapy consisting of ex vivo expanded IL-2-activated NK cells combined with human anti-PD-1 antibody as an important checkpoint molecule in a xenograft gastric cancer mouse model. EBV-LCL cell is used as a feeder to promote NK cell proliferation with a purity of 93.4%. Mice (NOG, female, 6–8 weeks old) with xenograft gastric tumors were treated with PBS, ex vivo IL-2-activated NK cells, IL-2-activated NK cell along with human anti-PD-1 (Nivolumab), and IL-2-activated pretreated NK cells with anti-PD-1 antibody. The cytotoxicity of ex vivo expanded NK cells against MKN-45 cells was assessed by a lactate dehydrogenase (LDH) assay. Tumor volume was evaluated for morphometric properties, and tumor-infiltrating NK cells were assessed by immunohistochemistry (IHC) and quantified by flow cytometry. Pathologic responses were considered by H and E staining. Ex vivo LDH evaluation showed the cytotoxic potential of treated NK cells against gastric cancer cell line. We indicated that the adoptive transfer of ex vivo IL-2-activated NK cells combined with anti-PD-1 resulted in tumor growth inhibition in a xenograft gastric cancer model. Mitotic count was significantly decreased (*p < 0.05), and the tumor was associated with improved infiltration of NK cells in the NK-anti-PD-1 pretreated group (*p < 0.05). In conclusion, the combination approach of activated NK cells and anti-PD-1 therapy results in tumor growth inhibition, accompanied by tumor immune cell infiltration in the gastric tumor model.

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“…To more selectively stimulate iNKT cells, one could use the therapeutic glycosphingolipid, a-galactosylceramide (a-GalCer), which is an immunomodulatory drug that very potently and specifically stimulates iNKT cells (27). Although initial studies showed great promise in activating iNKT cells to induce antitumoral effects (27)(28)(29), numerous clinical trials with various patients with solid tumor have only shown partial and inconsistent responses (30)(31)(32)(33)(34). Explanations for these disparate results included the development of iNKT-cell anergy with multiple a-GalCer stimulations, the potential patient pool which included patients with established solid tumors, and induction of resistance within the tumor to activated iNKT cells.…”

Section: Introductionmentioning

confidence: 99%

Imaging α-GalCer–Activated iNKT Cells in a Hepatic Metastatic Environment

Babes

Shim

Kubes

2022

Cancer Immunology Research

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Patients with colorectal cancer frequently develop liver metastases after, and perhaps as a consequence of, lifesaving surgical resection of the primary tumor. This creates a potential opportunity for prophylactic metastatic treatment with novel immunostimulatory molecules. Here, we used state-of-the-art intravital imaging of an experimental liver metastasis model to visualize the early behavior and function of invariant natural killer T (iNKT) cells stimulated with α-galactosylceramide (α-GalCer). Intravenous α-GalCer prior to tumor cell seeding in the liver significantly inhibited tumor growth. However, some seeding tumor cells survived. A multiple dosing regimen reduced tumor burden and prolonged the life of mice, whereas tumors returned within 5 days after a single dose of α-GalCer. With multiple doses of α-GalCer, iNKT cells increased in number and granularity (as did NK cells). As a result, the total number of contacts and time in contact with tumors increased substantially. In the absence of iNKT cells, the beneficial effect of α-GalCer was lost. Robust cytokine production dissipated over time. Repeated therapy, even after cytokine dissipation, led to reduced tumor burden and prolonged survival. Serial transplantation of tumors exposed to α-GalCer–activated iNKT cells did not induce greater resistance, suggesting no obvious epigenetic or genetic immunoediting in tumors exposed to activated iNKT cells. Very few tumor cells expressed CD1d in this model, and as such, adding monomers of CD1d–α-GalCer further reduced tumor growth. The data suggest early and repeated stimulation of iNKT cells with α-GalCer could have direct therapeutic benefit for patients with colorectal cancer who develop metastatic liver disease.

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Targeting Natural Killer T Cells in Solid Malignancies

Cited by 16 publications

References 96 publications

Immune Profile of Blood, Tissue and Peritoneal Fluid: A Comparative Study in High Grade Serous Epithelial Ovarian Cancer Patients at Interval Debulking Surgery

Immune Profile of Blood, Tissue and Peritoneal Fluid: A Comparative Study in High Grade Serous Epithelial Ovarian Cancer Patients at Interval Debulking Surgery

Adaptive NK Cell Therapy Modulated by Anti-PD-1 Antibody in Gastric Cancer Model

Imaging α-GalCer–Activated iNKT Cells in a Hepatic Metastatic Environment

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