scholarly journals Black Raspberries Suppress Colorectal Cancer by Enhancing Smad4 Expression in Colonic Epithelium and Natural Killer Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Yi-Wen Huang ◽  
Chien-Wei Lin ◽  
Pan Pan ◽  
Tianjiao Shan ◽  
Carla Elena Echeveste ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Dietary Intervention ◽  
Nk Cell ◽  
Good Prognosis ◽  
Colonic Epithelium ◽  
Antitumor Effects ◽  
Black Raspberries ◽  
Smad4 Expression

Innate immune cells in the tumor microenvironment have been proposed to control the transition from benign to malignant stages. In many cancers, increased infiltration of natural killer (NK) cells associates with good prognosis. Although the mechanisms that enable NK cells to restrain colorectal cancer (CRC) are unclear, the current study suggests the involvement of Smad4. We found suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Moreover, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated ApcMin/+ mice and adenocarcinomas in AOM/DSS-treated mice. Other studies have shown that Smad4 loss or weak expression in colonic epithelium associates with poor survival in CRC patients. Therefore, targeting Smad4 in both colonic epithelium and NK cells could provide an excellent opportunity to manage CRC. Toward this end, we showed that dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in patients with FAP or CRC and in the two CRC mouse models. Also, benzoate metabolites of BRBs, such as hippurate, upregulated Smad4 and Gzmb expression that might enhance the cytotoxicity of primary human NK cells. Of note, increased levels of hippurate is a metabolomic marker of a healthy gut microbiota in humans, and hippurate also has antitumor effects. In conclusion, our study suggests a new mechanism for the action of benzoate metabolites derived from plant-based foods. This mechanism could be exploited clinically to upregulate Smad4 in colonic epithelium and NK cells, thereby delaying CRC progression.

scholarly journals Reovirus enhances cytotoxicity of natural killer cells against colorectal cancer via TLR3 pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shiqi Long ◽  
Yangzhuo Gu ◽  
Yuanyuan An ◽  
Xiaojin Lin ◽  
Xiaoqing Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Signaling Pathway ◽  
Cell Function ◽  
Nk Cell ◽  
Antitumor Effects ◽  
Downstream Signaling ◽  
Egfr Expression ◽  
Downstream Signaling Pathway

Abstract Background Cetuximab has been approved for use for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer (CRC). However, treatment with cetuximab has shown limited efficacy as a CRC monotherapy. In addition, natural killer (NK) cell function is known to be severely attenuated in cancer patients. The goal of this study was to develop a new strategy to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NK cells, in combination with cetuximab against CRC cells. Methods Ex vivo expanded NK cells were stimulated with reovirus, and reovirus-activated NK cells mediated ADCC assay were performed on CRC cells in combination with cetuximab. The synergistic antitumor effects of reovirus-activated NK cells and cetuximab were tested on DLD-1 tumor-bearing mice. Finally, Toll-like receptor 3 (TLR3) knockdown in NK cells, along with chemical blockade of TLR3/dsRNA complex, and inhibition of the TLR3 downstream signaling pathway, were performed to explore the mechanisms by which reovirus enhances NK cell cytotoxicity. Results We first confirmed that exposure of NK cells to reovirus enhanced their cytotoxicity in a dose-dependent manner.We then investigated whether reovirus-activated NK cells exposed to cetuximab-bound CRC cells exhibited greater anti-tumor efficacy than either monotherapy. Co-culture of CRC cell lines with reovirus-activated NK cells indicated that NK cytotoxicity was significantly higher in combination with cetuximab, regardless of KRAS mutation status or EGFR expression level. We also found that reovirus activation of NK cells, in conjunction with cetuximab, resulted in significantly stronger anti-tumor efficacy.Finally, TLR3 knockdown, inhibition of TLR3/dsRNA complex or TBK1/IKKε demonstrated that activation of NK cells by reovirus was dependent on TLR3 and its downstream signaling pathway. Conclusions This study demonstrated that combination treatment of reovirus-activated NK cells with cetuximab synergistically enhances their anti-tumor cytotoxicity, suggesting a strong candidate strategy for clinical treatment of CRC.

scholarly journals TREM2 promotes natural killer cell development in CD3−CD122+NK1.1+ pNK cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hwa-Youn Lee ◽  
Eun-Hee Lee ◽  
Jawoon Yi ◽  
Kon-Young Ji ◽  
Su-Man Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Inflammatory Responses ◽  
Bone Marrow Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Antitumor Effects ◽  
Hematopoietic Stem

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2) signaling is considered to regulate anti-inflammatory responses in macrophages, dendritic cell maturation, osteoclast development, induction of obesity, and Alzheimer’s disease pathogenesis. However, little is known regarding the effect of TREM2 on natural killer (NK) cells. Results Here, we demonstrated for the first time that CD3−CD122+NK1.1+ precursor NK (pNK) cells expressed TREM2 and their population increased in TREM2-overexpressing transgenic (TREM2-TG) mice compared with that in female C57BL/6 J wild type (WT) mice. Both NK cell-activating receptors and NK cell-associated genes were expressed at higher levels in various tissues of TREM2-TG mice than in WT mice. In addition, bone marrow-derived hematopoietic stem cells (HSCs) of TREM2-TG mice (TG-HSCs) successfully differentiated into NK cells in vitro, with a higher yield from TG-HSCs than from WT-HSCs. In contrast, TREM2 signaling inhibition by TREM2-Ig or a phosphatidylinositol 3-kinase (PI3K) inhibitor affected the expression of the NK cell receptor repertoire and decreased the expression levels of NK cell-associated genes, resulting in significant impairment of NK cell differentiation. Moreover, in melanoma-bearing WT mice, injection of bone marrow cells from TREM2-TG mice exerted greater antitumor effects than that with cells from WT control mice. Conclusions Collectively, our data clearly showed that TREM2 promoted NK cell development and tumor regression, suggesting TREM2 as a new candidate for cancer immunotherapy.

Engineering chimeric antigen receptor-natural killer cells for cancer immunotherapy

Immunotherapy ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 653-664 ◽  
Author(s):  
Yu Zhao ◽  
Xiaorong Zhou
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Structural Characteristics ◽  
Antigen Receptor ◽  
Adoptive Cell Transfer ◽  
Antitumor Effects ◽  
Treatment Regimens ◽  
Existing Problems

Adoptive cell transfer has attracted considerable attention as a treatment for cancer. The success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for the treatment of haematologic tumors has demonstrated the potential of CAR. In this review, we describe the current CAR-engineered natural killer (CAR-NK) cell construction strategies, including the design principles and structural characteristics of the extracellular, transmembrane and intracellular regions of the CAR structure. In addition, we review different cellular carriers used to develop CAR-NK cells, highlighting existing problems and challenges. We further discuss possible ways to optimize CAR from the perspective of the tumor microenvironment to harness the strength of CAR-NK cells and provided rationales to combine CAR-NK cells with other treatment regimens to enhance antitumor effects.

scholarly journals Cross-Talk Between Tumor Cells Undergoing Epithelial to Mesenchymal Transition and Natural Killer Cells in Tumor Microenvironment in Colorectal Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Ana Vuletić ◽  
Katarina Mirjačić Martinović ◽  
Nevena Tišma Miletić ◽  
Jerome Zoidakis ◽  
Sergi Castellvi-Bel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Cross Talk ◽  
Immune Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Nk Cell ◽  
Mesenchymal Transition

Tumor cells undergoing epithelial to mesenchymal transition (EMT) and immune cells in tumor microenvironment (TME) reciprocally influence each other. Immune cells, by supplying TME with bioactive molecules including cytokines, chemokines, enzymes, metabolites, and by physical interactions with tumor cells via their receptors, represent an important factor that affects EMT. Chronical inflammation in TME favorizes tumor growth and invasiveness and stimulates synthesis of EMT promoting transcription factors. Natural killer (NK) cells, owing to their unique ability to exert cytotoxic function independent of major histocompatibility (MHC)-mediated antigen presentation, play a significant role in the control of metastasis in colorectal cancer (CRC). Although, the cross-talk between immune cells and tumor cells in general favors the induction of EMT and inhibition of antitumor immune responses, there are some changes in the immunogenicity of tumor cells during EMT of CRC cells that increase their susceptibility to NK cell cytotoxic lysis. However, suppressive TME downmodulates the expression of activating NK cell receptors, decreases the expression of activating and increases the expression of inhibitory NK cell ligands on tumor cells, and impairs NK cell metabolism that altogether negatively affects the overall NK cell function. Furthermore, process of EMT is often associated with increased expression of programmed cell death ligand (PD-L) and expression of immune checkpoint molecules PD-1, TIGIT, and TIM3 on functionally exhausted NK cells in TME in CRC. In this review we discuss modalities of cross-talk between tumor cells and NK cells, with regard of EMT-driven changes.

Facile discovery of a therapeutic agent for NK-mediated synergistic antitumor effects using a patient-derived 3D platform

2022 ◽  
Author(s):  
Young Eun Lee ◽  
Chae Min Yuk ◽  
Min Seok Lee ◽  
Ki-Cheol Han ◽  
Eunsung Jun ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Treatment ◽  
Nk Cells ◽  
Natural Killer ◽  
Therapeutic Agent ◽  
Nk Cell ◽  
Physical Barrier ◽  
Antitumor Effects ◽  
Cell Dysfunction

Despite the essential roles of natural killer (NK) cells in cancer treatment, the physical barrier and biological cues of the tumor microenvironment (TME) may induce NK cell dysfunction, causing their...

scholarly journals TREM2 Promotes Natural Killer Cell Development in CD3-CD122+NK1.1+ pNK Cells

2020 ◽  
Author(s):  
Hwa-Youn Lee ◽  
Eun-Hee Lee ◽  
Jawoon Yi ◽  
Kon-Young Ji ◽  
Su-Man Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Inflammatory Responses ◽  
Bone Marrow Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Antitumor Effects ◽  
Hematopoietic Stem

Abstract Background: Triggering receptor expressed on myeloid cells 2 (TREM2) signaling is considered to regulate anti-inflammatory responses in macrophages, dendritic cell maturation, osteoclast development, induction of obesity, and Alzheimer’s disease pathogenesis. However, little is known regarding the effect of TREM2 on natural killer (NK) cells.Results: Here, we demonstrated for the first time that CD3-CD122+NK1.1+ precursor NK (pNK) cells expressed TREM2 and their population increased in TREM2-overexpressing transgenic (TREM2-TG) mice compared with that in female C57BL/6J wild type (WT) mice. Both NK cell-activating receptors and NK cell-associated genes were expressed at higher levels in various tissues of TREM2-TG mice than in WT mice. In addition, bone marrow-derived hematopoietic stem cells (HSCs) of TREM2-TG mice (TG-HSCs) successfully differentiated into NK cells in vitro, with a higher yield from TG-HSCs than from WT-HSCs. In contrast, TREM2 signaling inhibition by TREM2-Ig or a phosphatidylinositol 3-kinase (PI3K) inhibitor affected the expression of the NK cell receptor repertoire and decreased the expression levels of NK cell-associated genes, resulting in significant impairment of NK cell differentiation. Moreover, in melanoma-bearing WT mice, injection of bone marrow cells from TREM2-TG mice exerted greater antitumor effects than that with cells from WT control mice.Conclusions: Collectively, our data clearly showed that TREM2 promoted NK cell development and tumor regression, suggesting TREM2 as a new candidate for cancer immunotherapy.

Preclinical study of adoptive immunotherapy with natural killer cells in metastatic colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13103-e13103
Author(s):  
Silvia Brugnatelli ◽  
Ilaria Turin ◽  
Mariangela Manzoni ◽  
Marcello Maestri ◽  
Enrica Montini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Data Monitoring Committee ◽  
Adcc Assay

e13103 Background: Several immune-based approaches for treatment of metastatic colorectal cancer (mCRC) are currently under investigation. Aims of our study were to grow and characterize tumor cells (TC) obtained from mCRC patients, and to investigate their susceptibility to autologous natural killer (NK) cell recognition and killing in vitro. Methods: Tumor samples and peripheral blood mononuclear cells from 10 mCRC patients undergoing surgery were collected. Establishment of TC lines that are representative of the original tumor and could be expanded in vitro for a significant number of passage was performed according with our previously described method (Turin I et al, Cytotherapy 2007). CD56+CD3- NK cells were incubated overnight with medium alone or activated with IL-2 (100U/ml) or IL-15 (20ng/ml) and tested against 51Cr-labeled primary TC in NK assay or in ADCC assay after pre-coating of TC with anti-EGFR monoclonal antibody cetuximab. Results: Eight stable mCRC lines have been obtained and characterized to confirm their neoplastic origin. Patient NK cells display low capacity to lyse autologous TC (median 12%, range 5%-17%). IL-2 and IL-15 incubation significantly potentiate NK cytotoxic capacity (median18%, range 6%-62% and median 35%, range 28%-65%, respectively). These results refer to an effector:target ratio of 25:1. ADCC assay has shown that cetuximab pre-coating of TC results on an increasing of their susceptibility to NK-mediated lysis. Phenotypical and molecular analysis of activating NK receptors and their ligands present on surface of TC are currently under evaluation. Conclusions: NK cells derived from mCRC patients display measurable cytotoxic activity against autologous primary TC. Susceptibility of NK-mediated lysis is strongly enhanced by pre-incubation of NK cell with cytokines and by pre-coating of TC with cetuximab. These findings, presented upon approval by the study’s data monitoring committee and undergoing confirmation in a larger series, may support a pilot study of NK cells pre-activated ex vivo for treatment of mCRC patients.

scholarly journals Resveratrol Activates Natural Killer Cells through Akt- and mTORC2-Mediated c-Myb Upregulation

2020 ◽  
Vol 21 (24) ◽  
pp. 9575
Author(s):  
Yoo-Jin Lee ◽  
Jongsun Kim
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Reaction Pathway ◽  
Synergistic Effects ◽  
Cytolytic Activity ◽  
Antitumor Effects ◽  
Potential Health

Natural killer (NK) cells are suitable targets for cancer immunotherapy owing to their potent cytotoxic activity. To maximize the therapeutic efficacy of cancer immunotherapy, adjuvants need to be identified. Resveratrol is a well-studied polyphenol with various potential health benefits, including antitumor effects. We previously found that resveratrol is an NK cell booster, suggesting that it can serve as an adjuvant for cancer immunotherapy. However, the molecular mechanism underlying the activation of NK cells by resveratrol remains unclear. The present study aimed to determine this mechanism. To this end, we investigated relevant pathways in NK cells using Western blot, real-time polymerase chain reaction, pathway inhibitor, protein/DNA array, and cytotoxicity analyses. We confirmed the synergistic effects of resveratrol and interleukin (IL)-2 on enhancing the cytolytic activity of NK cells. Resveratrol activated Akt by regulating Mammalian Target of Rapamycin (mTOR) Complex 2 (mTORC2) via phosphatase and tensin homolog (PTEN) and ribosomal protein S6 kinase beta-1 (S6K1). Moreover, resveratrol-mediated NK cell activation was more dependent on the mTOR pathway than the Akt pathway. Importantly, resveratrol increased the expression of c-Myb, a downstream transcription factor of Akt and mTORC2. Moreover, c-Myb was essential for resveratrol-induced NK cell activation in combination with IL-2. Our results demonstrate that resveratrol activates NK cells through Akt- and mTORC2-mediated c-Myb upregulation.

scholarly journals Prognostic Value of Interleukin-32 Expression and Its Correlation with the Infiltration of Natural Killer Cells in Cutaneous Melanoma

2021 ◽  
Vol 10 (20) ◽  
pp. 4691
Author(s):  
Ji Young Kang ◽  
Kyung Eun Kim
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cutaneous Melanoma ◽  
Prognostic Value ◽  
Nk Cell ◽  
Predictive Biomarker ◽  
Good Prognosis ◽  
Strong Positive Correlation ◽  
Effector Cells ◽  
Kaplan Meier

Interleukin-32 (IL-32) is well known as a proinflammatory cytokine that is expressed in various immune cells and cancers. However, the clinical relevance of IL-32 expression in cutaneous melanoma has not been comprehensively studied. Here, we identified the prognostic value of IL32 expression using various systematic multiomic analyses. The IL32 expressions were significantly higher in cutaneous melanoma than in normal tissue, and Kaplan–Meier survival analysis showed a correlation between IL32 expression and good prognosis in cutaneous melanoma patients. In addition, we analyzed the correlation between IL32 expression and the infiltration of natural killer (NK) cells to identify a relevant mechanism between IL32 expression and prognosis in cutaneous melanoma (p = 0.00031). In the relationship between IL32 expression and the infiltration of NK cells, a negative correlation was found in resting NK cells (rho = −0.38, p = 3.95 × 10−17) whereas a strong positive correlation was observed only in active NK cells (rho = 0.374, p = 1.23 × 10−16). Moreover, IL32 expression was markedly positively correlated with the cytolytic molecules, such as granzyme and perforin. These data suggest that IL32 expression may increase patient survival through the infiltration and activation of NK cells, representative anticancer effector cells, in cutaneous melanoma. Collectively, this study provides the prognostic value of IL32 expression and its potential role as an effective predictive biomarker for NK cell infiltration in cutaneous melanoma.

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