The Immunomodulation Potential of Exosomes in Tumor Microenvironment

Exosomes are lipid bilayer particles that originated from almost all types of cells and play an important role in intercellular communication. Tumor-derived exosomes contain large amounts of noncoding RNA, DNA, and proteins, which can be transferred into recipient cells as functional components in exosomes. These exosomal functional constituents depend on the originating cells, and it has been proved that types and numbers of exosomal components differ in cancer patients and healthy individuals. This review summarizes the role of tumor-derived exosomes in immunomodulation and discusses the application of exosomes in immunotherapy in cancers. Overall, exosomes isolated from cancer cells are turned out to promote immune evasion and interfere with immune responses in tumors through inducing apoptosis of CD8+ T cells, facilitating generation of Tregs, suppressing natural killer (NK) cell cytotoxicity, inhibiting maturation and differentiation of monocyte, and enhancing suppressive function of myeloid-derived suppressor cells (MDSCs). Mechanistically, exosomal functional components play a significant role in the immunomodulation in cancers. Moreover, based on the existing studies, exosomes could potentially serve as therapeutic delivery vehicles, noninvasive biomarkers, and immunotherapeutic vaccines for various types of cancers.

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α-Pinene Enhances the Anticancer Activity of Natural Killer Cells via ERK/AKT Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22020656 ◽

2021 ◽

Vol 22 (2) ◽

pp. 656

Author(s):

Hantae Jo ◽

Byungsun Cha ◽

Haneul Kim ◽

Sofia Brito ◽

Byeong Mun Kwak ◽

...

Keyword(s):

Nk Cells ◽

Cancer Cells ◽

Natural Killer ◽

Nk Cell ◽

Granzyme B ◽

Akt Pathway ◽

Cell Cytotoxicity ◽

Anticancer Effects ◽

Nk Cell Cytotoxicity

Natural killer (NK) cells are lymphocytes that can directly destroy cancer cells. When NK cells are activated, CD56 and CD107a markers are able to recognize cancer cells and release perforin and granzyme B proteins that induce apoptosis in the targeted cells. In this study, we focused on the role of phytoncides in activating NK cells and promoting anticancer effects. We tested the effects of several phytoncide compounds on NK-92mi cells and demonstrated that α-pinene treatment exhibited higher anticancer effects, as observed by the increased levels of perforin, granzyme B, CD56 and CD107a. Furthermore, α-pinene treatment in NK-92mi cells increased NK cell cytotoxicity in two different cell lines, and immunoblot assays revealed that the ERK/AKT pathway is involved in NK cell cytotoxicity in response to phytoncides. Furthermore, CT-26 colon cancer cells were allografted subcutaneously into BALB/c mice, and α-pinene treatment then inhibited allografted tumor growth. Our findings demonstrate that α-pinene activates NK cells and increases NK cell cytotoxicity, suggesting it is a potential compound for cancer immunotherapy.

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PRESENCE OF FcR FOR IgG AND IgM ON HUMAN NK CELLS: THE ROLE OF IMMUNE COMPLEXES IN THE REGULATION OF NK CELL CYTOTOXICITY

NK Cells and Other Natural Effector Cells ◽

10.1016/b978-0-12-341360-4.50099-8 ◽

1982 ◽

pp. 631-637 ◽

Cited By ~ 2

Author(s):

Jean E. Merrill ◽

Sidney Golub ◽

Mikael Jondal ◽

Fred Lanefeldt ◽

Bertil Fredholm

Keyword(s):

Nk Cells ◽

Immune Complexes ◽

Nk Cell ◽

Cell Cytotoxicity ◽

Nk Cell Cytotoxicity

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Nonstochastic Coexpression of Activation Receptors on Murine Natural Killer Cells

Journal of Experimental Medicine ◽

10.1084/jem.191.8.1341 ◽

2000 ◽

Vol 191 (8) ◽

pp. 1341-1354 ◽

Cited By ~ 97

Author(s):

Hamish R.C. Smith ◽

Hubert H. Chuang ◽

Lawrence L. Wang ◽

Margarita Salcedo ◽

Jonathan W. Heusel ◽

...

Keyword(s):

Natural Killer Cells ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Inhibitory Receptors ◽

Antigen Receptors ◽

Killer Cells ◽

Histocompatibility Complex ◽

Nk Cell Cytotoxicity

Murine natural killer cells (NK) express lectin-like activation and inhibitory receptors, including the CD94/NKG2 family of receptors that bind Qa-1, and the Ly-49 family that recognizes major histocompatibility complex class I molecules. Here, we demonstrate that cross-linking of NK cells with a new specific anti–Ly-49H mAb induced NK cell cytotoxicity and cytokine production. Ly-49H is expressed on a subset of NK cells and can be coexpressed with Ly-49 inhibitory receptors. However, unlike Ly-49 inhibitory receptors, Ly-49H is not detectable on naive splenic CD3+ T cells, indicating that Ly-49H may be an NK cell–specific activation receptor. In further contrast to the stochastically expressed Ly-49 inhibitory receptors, Ly-49H is preferentially expressed with the Ly-49D activation receptor, and expression of both Ly-49H and Ly-49D is augmented on NK cells that lack receptors for Qa-1 tetramers. On developing splenic NK1.1+ cells, Ly-49D and Ly-49H are expressed later than the inhibitory receptors. These results directly demonstrate that Ly-49H activates primary NK cells, and suggest that expression of Ly-49 activation receptors by NK cells may be specifically regulated on NK cell subsets. The simultaneous expression of multiple activation receptors by individual NK cells contrasts with that of T cell antigen receptors and is relevant to the role of NK cells in innate immunity.

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The Role of Interleukin-15 on Natural Killer Cell Homeostasis and Activity in Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v112.11.2574.2574 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2574-2574

Author(s):

Mi roslaw J Szczepanski ◽

Malgorzata Czystowska ◽

Marta E Szajnik ◽

Magis Mandapathil ◽

Benedict Hilldorfer ◽

...

Keyword(s):

Nk Cells ◽

Myeloid Leukemia ◽

Nk Cell ◽

Intensive Chemotherapy ◽

Interleukin 15 ◽

The Mean ◽

Nk Cell Cytotoxicity ◽

Anti Tumor Activity ◽

Acute Myeloid

Abstract Interleukin-15 (IL-15) has been demonstrated to play a critical role in the regulation of natural killer (NK) cells. IL-15 induces the differentiation of NK cells from hematopoietic progenitors, stimulates the expansion of peripheral NK cells, and supports their survival. We investigated the role of IL-15 as a homeostatic regulator of NK cells in 29 patients diagnosed with acute myeloid leukemia (AML) and the potential role of IL-15 in enhancing the anti-tumor activity of NK cells in AML patients. The percentage of circulating NK cells was lower (p<0.0001) in the AML patients (6%± 0.7, range 1–17%) compared to the NK cells of healthy donors (12%± 1, range 9–17 %). At diagnosis the mean level of IL-15 in patient plasma was 1.9 pg/ml (range 0.03–8.9) and increased (p <0.02) to 5.2 pg/ml (range 0.06–13.4) after the completion of induction chemotherapy, when the NK levels had been reduced to zero cells/microliter. The mean level of IL-15 subsequently decreased to pre-treatment levels in the AML patients who achieved complete remission (mean 1.6 pg/ml, range 0.4–2.3). To assess effects of IL-15 on the NK cytotoxicity, we sorted NK cells from PBMC obtained from AML patients prior to treatment (at diagnosis) and cultured them in the presence of IL-15. Following IL-15 stimulation, a significant increase in NK-cell cytotoxicity against K562 targets and the patients’ autologous leukemic blasts was observed (p<0.05) as was up-regulation in expression of the activating natural cytotoxicity receptors, NKp30 and NKp46 and the C-type lectin receptors NKG2D and NKG2C (p<0.02–0.001). Addition of blocking antibodies to the activating receptors reduced NK-cell cytotoxicity. We determined that IL-15, a homeostatic NK-cell cytokine, increases after severe depletion of NK cells following intensive chemotherapy and this leads to increased NK-cell lytic activity in AML patients. These data suggest that modulation of IL-15 levels in AML could be therapeutically beneficial as IL-15 enhances NK-cell recovery following intensive chemotherapy and increases NK-cell anti-tumor activity.

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Escape of HIV-1-Infected Dendritic Cells from TRAIL-Mediated NK Cell Cytotoxicity during NK-DC Cross-Talk—A Pivotal Role of HMGB1

PLoS Pathogens ◽

10.1371/journal.ppat.1000862 ◽

2010 ◽

Vol 6 (4) ◽

pp. e1000862 ◽

Cited By ~ 46

Author(s):

Marie-Thérèse Melki ◽

Héla Saïdi ◽

Alexandre Dufour ◽

Jean-Christophe Olivo-Marin ◽

Marie-Lise Gougeon

Keyword(s):

Dendritic Cells ◽

Cross Talk ◽

Nk Cell ◽

Pivotal Role ◽

Cell Cytotoxicity ◽

Nk Cell Cytotoxicity ◽

Hiv 1

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Intrinsic Resistance of Chronic Lymphocytic Leukemia Cells to NK Cell-Mediated Lysis Can Be Overcome In Vitro by Pharmacological Inhibition of Cdc42-Induced Actin Cytoskeleton Remodeling

Frontiers in Immunology ◽

10.3389/fimmu.2021.619069 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hannah Wurzer ◽

Liza Filali ◽

Céline Hoffmann ◽

Max Krecke ◽

Andrea Michela Biolato ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Actin Cytoskeleton ◽

Nk Cells ◽

Nk Cell ◽

Granzyme B ◽

Lymphocytic Leukemia ◽

Cell Cytotoxicity ◽

Cytoskeleton Remodeling ◽

Nk Cell Cytotoxicity

Natural killer (NK) cells are innate effector lymphocytes with strong antitumor effects against hematologic malignancies such as chronic lymphocytic leukemia (CLL). However, NK cells fail to control CLL progression on the long term. For effective lysis of their targets, NK cells use a specific cell-cell interface, known as the immunological synapse (IS), whose assembly and effector function critically rely on dynamic cytoskeletal changes in NK cells. Here we explored the role of CLL cell actin cytoskeleton during NK cell attack. We found that CLL cells can undergo fast actin cytoskeleton remodeling which is characterized by a NK cell contact-induced accumulation of actin filaments at the IS. Such polarization of the actin cytoskeleton was strongly associated with resistance against NK cell-mediated cytotoxicity and reduced amounts of the cell-death inducing molecule granzyme B in target CLL cells. Selective pharmacological targeting of the key actin regulator Cdc42 abrogated the capacity of CLL cells to reorganize their actin cytoskeleton during NK cell attack, increased levels of transferred granzyme B and restored CLL cell susceptibility to NK cell cytotoxicity. This resistance mechanism was confirmed in primary CLL cells from patients. In addition, pharmacological inhibition of actin dynamics in combination with blocking antibodies increased conjugation frequency and improved CLL cell elimination by NK cells. Together our results highlight the critical role of CLL cell actin cytoskeleton in driving resistance against NK cell cytotoxicity and provide new potential therapeutic point of intervention to target CLL immune escape.

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Differential Role of p38 and c-Jun N-Terminal Kinase 1 Mitogen-Activated Protein Kinases in NK Cell Cytotoxicity

The Journal of Immunology ◽

10.4049/jimmunol.165.4.1782 ◽

2000 ◽

Vol 165 (4) ◽

pp. 1782-1789 ◽

Cited By ~ 56

Author(s):

Rossana Trotta ◽

Katia Fettucciari ◽

Livio Azzoni ◽

Bekele Abebe ◽

Kristin A. Puorro ◽

...

Keyword(s):

Protein Kinases ◽

Nk Cell ◽

Cell Cytotoxicity ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein ◽

Nk Cell Cytotoxicity

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Case Report: Characterizing the Role of the STXBP2-R190C Monoallelic Mutation Found in a Patient With Hemophagocytic Syndrome and Langerhans Cell Histiocytosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.723836 ◽

2021 ◽

Vol 12 ◽

Author(s):

Laura Viñas-Giménez ◽

Rafael Rincón ◽

Roger Colobran ◽

Xavier de la Cruz ◽

Verónica Paola Celis ◽

...

Keyword(s):

Cell Line ◽

Langerhans Cell Histiocytosis ◽

Nk Cell ◽

Adaptive Immune System ◽

Langerhans Cell ◽

Adaptive Immune ◽

Life Threatening ◽

Monoallelic Mutation ◽

Nk Cell Cytotoxicity

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder. HLH can be considered as a threshold disease depending on the trigger and the residual NK-cell cytotoxicity. In this study, we analyzed the molecular and functional impact of a novel monoallelic mutation found in a patient with two episodes of HLH. A 9-month-old child was diagnosed at 2 months of age with cutaneous Langerhans cell histiocytosis (LCH). After successful treatment, the patient developed an HLH episode. At 16 month of age, the patient went through an HSCT losing the engraftment 5 months later concomitant with an HLH relapse. The genetic study revealed a monoallelic mutation in the STXBP2 gene (.pArg190Cys). We transfected COS7 cells to analyze the STXBP2-R190C expression and to test the interaction with STX11. We used the RBL-2H3 cell line expressing STXBP2-WT-EGFP or R190C-EGFP for degranulation assays. Mutation STXBP2-R190C did not affect protein expression or interaction with syntaxin-11. However, we have demonstrated that STXBP2-R190C mutation diminishes degranulation in the RBL-2H3 cell line compared with the RBL-2H3 cell line transfected with STXBP2-WT or nontransfected. These results suggest that STXBP2-R190C mutation acts as a modifier of the degranulation process producing a decrease in degranulation. Therefore, under homeostatic conditions, the presence of one copy of STXBP2-R190 could generate sufficient degranulation capacity. However, it is likely that early in life when adaptive immune system functions are not sufficiently developed, an infection may not be resolved with this genetic background, leading to a hyperinflammation syndrome and eventually develop HLH. This analysis highlights the need for functional testing of new mutations to validate their role in genetic susceptibility and to establish the best possible treatment for these patients.

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