TRAIL/DR5 Plays a Critical Role in NK Cell-Mediated Negative Regulation of Dendritic Cell Cross-Priming of T Cells

It has recently been demonstrated that in vivo administration of murine interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhancement of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 against a number of murine tumors has been evaluated. Experimental pulmonary metastases or subcutaneous growth of the B16F10 melanoma were markedly reduced in mice treated intraperitoneally with IL-12, resulting in an increase in survival time. The therapeutic effectiveness of IL-12 was dose dependent and treatment of subcutaneous tumors could be initiated up to 14 d after injection of tumor cells. Likewise, established experimental hepatic metastases and established subcutaneous M5076 reticulum cell sarcoma and Renca renal cell adenocarcinoma tumors were effectively treated by IL-12 at doses which resulted in no gross toxicity. Local peritumoral injection of IL-12 into established subcutaneous Renca tumors resulted in regression and complete disappearance of these tumors. IL-12 was as effective in NK cell-deficient beige mice or in mice depleted of NK cell activity by treatment with antiasialo GM1, suggesting that NK cells are not the primary cell type mediating the antitumor effects of this cytokine. However, the efficacy of IL-12 was greatly reduced in nude mice suggesting the involvement of T cells. Furthermore, depletion of CD8+ but not CD4+ T cells significantly reduced the efficacy of IL-12. These results demonstrate that IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating the antitumor effects against subcutaneous tumors.

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Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

Journal of Translational Medicine ◽

10.1186/s12967-021-03203-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Hee Young Na ◽

Yujun Park ◽

Soo Kyung Nam ◽

Jiwon Koh ◽

Yoonjin Kwak ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

B Cells ◽

Nk Cells ◽

Natural Killer ◽

Immune Cells ◽

Nk Cell ◽

Critical Role ◽

Killer Cell ◽

Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

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The Role of Dendritic Cells in TB and HIV Infection

Journal of Clinical Medicine ◽

10.3390/jcm9082661 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2661

Author(s):

Rachel Abrahem ◽

Emerald Chiang ◽

Joseph Haquang ◽

Amy Nham ◽

Yu-Sam Ting ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Dendritic Cells ◽

Dendritic Cell ◽

Hiv Infection ◽

Cell Response ◽

Defense Mechanism ◽

Critical Role ◽

Cytokine Release ◽

T Helper 1

Dendritic cells are the principal antigen-presenting cells (APCs) in the host defense mechanism. An altered dendritic cell response increases the risk of susceptibility of infections, such as Mycobacterium tuberculosis (M. tb), and the survival of the human immunodeficiency virus (HIV). The altered response of dendritic cells leads to decreased activity of T-helper-1 (Th1), Th2, Regulatory T cells (Tregs), and Th17 cells in tuberculosis (TB) infections due to a diminishment of cytokine release from these APCs, while HIV infection leads to DC maturation, allowing DCs to migrate to lymph nodes and the sub-mucosa where they then transfer HIV to CD4 T cells, although there is controversy around this topic. Increases in the levels of the antioxidant glutathione (GSH) plays a critical role in maintaining dendritic cell redox homeostasis, leading to an adequate immune response with sufficient cytokine release and a subsequent robust immune response. Thus, an understanding of the intricate pathways involved in the dendritic cell response are needed to prevent co-infections and co-morbidities in individuals with TB and HIV.

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NKG2D Polymorphism in Melanoma Patients from Southeastern Spain

Cancers ◽

10.3390/cancers11040438 ◽

2019 ◽

Vol 11 (4) ◽

pp. 438 ◽

Cited By ~ 1

Author(s):

Lourdes Gimeno ◽

Helios Martínez-Banaclocha ◽

M. Bernardo ◽

José Bolarin ◽

Luis Marín ◽

...

Keyword(s):

T Cells ◽

Natural Killer ◽

Cd8 T Cells ◽

Nk Cell ◽

Critical Role ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Southeastern Spain ◽

Melanoma Patients ◽

Risk Of Cancer

Background: Natural killer (NK) and CD8+ T cells are involved in the immune response against melanoma. C-Type lectin-like NK cell receptors are located in the Natural Killer Complex (NKC) region 12p13.2-p12.3 and play a critical role in regulating the activity of NK and CD8+ T cells. An association between polymorphisms in the NKC region, including the NKG2D gene and NKG2A promoter, and the risk of cancer has been previously described. The aim of this study was to analyze the association of polymorphisms in the NKC region with cutaneous melanoma in patients from southeastern Spain. Methods: Seven single-nucleotide polymorphisms (SNPs) in the NKG2D gene (NKC3,4,7,9,10,11,12), and one SNP in the NKG2A promoter (NKC17) were genotyped by a TaqMan 5′ Nuclease Assay in 233 melanoma patients and 200 matched healthy controls. Results: A linkage disequilibrium analysis of the SNPs performed in the NKC region revealed two blocks of haplotypes (Hb-1 and Hb-2) with 14 and seven different haplotype subtypes, respectively. The third most frequent haplotype from the block Hb-2—NK3 (CAT haplotype)—was significantly more frequent on melanoma patients than on healthy controls (p = 0.00009, Pc = 0.0006). No further associations were found when NKC SNPs were considered independently. Conclusions: Our results suggest an association between NKG2D polymorphisms and the risk of cutaneous malignant melanoma.

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Sequential Anti-PD1 Therapy Following Dendritic Cell Vaccination Improves Survival in a HER2 Mammary Carcinoma Model and Identifies a Critical Role for CD4 T Cells in Mediating the Response

Frontiers in Immunology ◽

10.3389/fimmu.2019.01939 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 11

Author(s):

Krithika N. Kodumudi ◽

Ganesan Ramamoorthi ◽

Colin Snyder ◽

Amrita Basu ◽

Yongsheng Jia ◽

...

Keyword(s):

T Cells ◽

Dendritic Cell ◽

Mammary Carcinoma ◽

Cd4 T Cells ◽

Critical Role ◽

Dendritic Cell Vaccination

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Dendritic Cell-Based Vaccines Positively Impact Natural Killer and Regulatory T Cells in Hepatocellular Carcinoma Patients

Clinical and Developmental Immunology ◽

10.1155/2011/249281 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 20

Author(s):

Sarah M. Bray ◽

Lazar Vujanovic ◽

Lisa H. Butterfield

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Dendritic Cell ◽

Regulatory T Cells ◽

Cell Activation ◽

Nk Cell ◽

Effector Cells ◽

Dc Vaccine ◽

The Impact

Immunotherapy of cancer must promote antitumor effector cells for tumor eradication as well as counteract immunoregulatory mechanisms which inhibit effectors. Immunologic therapies of cancer are showing promise, including dendritic cell-(DC-) based strategies. DC are highly malleable antigen-presenting cells which can promote potent antitumor immunity as well as tolerance, depending on the environmental signals received. Previously, we tested a peptide-pulsed DC vaccine to promote Alpha-fetoprotein (AFP-) specific anti-tumor immunity in patients with hepatocellular carcinoma (HCC), and reported on the CD8+T cell responses induced by this vaccine and the clinical trial results. Here, we show that the peptide-loaded DC enhanced NK cell activation and decreased regulatory T cells (Treg) frequencies in vaccinated HCC patients. We also extend these data by testing several forms of DC vaccinesin vitroto determine the impact of antigen loading and maturation signals on both NK cells and Treg from healthy donors and HCC patients.

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Regulatory T Cells Control Dendritic Cell/NK Cell Cross-Talk in Lymph Nodes at the Steady State by Inhibiting CD4+ Self-Reactive T Cells

The Journal of Immunology ◽

10.4049/jimmunol.180.7.4679 ◽

2008 ◽

Vol 180 (7) ◽

pp. 4679-4686 ◽

Cited By ~ 59

Author(s):

Magali Terme ◽

Nathalie Chaput ◽

Behazine Combadiere ◽

Averil Ma ◽

Toshiaki Ohteki ◽

...

Keyword(s):

T Cells ◽

Steady State ◽

Dendritic Cell ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Cross Talk ◽

Nk Cell

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Depletion of Regulatory T Cells Dramatically Improves DC-Based Immunization Against Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v108.11.3694.3694 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3694-3694 ◽

Cited By ~ 1

Author(s):

Stephanie Delluc ◽

Auguste Gaston ◽

Carmen Marchiol-Fournigault ◽

Didier Fradelizi ◽

Armelle Regnault ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Acute Myeloid Leukemia ◽

Cd4 T Cells ◽

Myeloid Leukemia ◽

Nk Cell ◽

Critical Role ◽

Dramatic Improvement ◽

Acute Myeloid

Abstract Dendritic cell (DC)-based vaccination is a promising approach to enhance anti-tumor immunity that could be considered for patients with high risk acute myeloid leukemia (AML). We have already shown in human that DC pulsed with eluted peptides (EP) from autologous AML blasts (DC/EP) are able to induce CD4+ and CD8+ anti-leukemic immune response in vitro (Delluc S, Haematologica, 2005). In order to optimize this vaccination strategy for AML patients we developed a pre-clinical murine model. C57/Bl6 mice were vaccinated by DC pulsed or not with peptides eluted from the syngenic C1498 myelomonocytic leukemic cell line in a prophylactic setting. Injection of DC/EP induced an anti-leukemic response as shown by the cytotoxic activity of CD4 T cells, whereas the injection of unpulsed DC induced a NK cell-mediated cytotoxicity against C1498 cells. In vivo depletion of CD4 T cells or NK cells abrogated the protective effect induced by DC/EP (p=0.02) or DC (p=0.06) vaccination, respectively, confirming their critical role in preventing leukemic outgrowth. However, late C1498 re-challenge showed that the anti-leukemic immune response was insufficient to protect DC/EP vaccinated mice from death, suggesting an ineffective or absent long-lived memory response. Since several populations of T cells have regulatory properties potentially inhibiting anti-tumor responses, we hypothesized that CD25+ cell-depletion in vivo could enhance the protection induced by vaccination. Indeed, we observed a dramatic improvement of the survival of mice treated by an anti-CD25 antibody before vaccination compared to mice vaccinated by DC/EP alone (p<0.01). More interestingly, CD25 depletion allowed the generation of long-lived immune responses since mice were protected from a late re-challenge by C1498 cells. Our results strongly suggest that depletion of regulatory CD25 T cells before DC-based vaccination should be considered for immunotherapy of weakly immunogenic tumors such as AML.

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Involvement of SOCS3 in Regulation of CD11c+ Dendritic Cell-Derived Osteoclastogenesis and Severe Alveolar Bone Loss

Infection and Immunity ◽

10.1128/iai.01070-08 ◽

2009 ◽

Vol 77 (5) ◽

pp. 2000-2009 ◽

Cited By ~ 16

Author(s):

Xiaoxia Zhang ◽

Mawadda Alnaeeli ◽

Bhagirath Singh ◽

Yen-Tung A. Teng

Keyword(s):

T Cells ◽

Dendritic Cell ◽

Bone Loss ◽

Alveolar Bone ◽

Expression Profiles ◽

Critical Role ◽

Alveolar Bone Loss ◽

Cytokine Signaling ◽

Periodontal Inflammation ◽

Socs3 Expression

ABSTRACT To investigate the role of suppressor of cytokine signaling (SOCS) molecules in periodontal immunity and RANKL-mediated dendritic cell (DC)-associated osteoclastogenesis, we analyzed SOCS expression profiles in CD4+ T cells and the effect of SOCS3 expression in CD11c+ DCs during periodontal inflammation-induced osteoclastogenesis and bone loss in nonobese diabetic (NOD) versus humanized NOD/SCID mice. Our results of ex vivo and in vitro analyses showed that (i) there is significantly higher SOCS3 expression associated with RANKL+ T-cell-mediated bone loss in correlation with increased CD11c+ DC-mediated osteoclastogenesis; (ii) the transfection of CD11c+ DC using an adenoviral vector carrying a dominant negative SOCS3 gene significantly abrogates TRAP and bone-resorptive activity; and (iii) inflammation-induced TRAP expression, bone resorption, and SOCS3 activity are not associated with any detectable change in the expression levels of TRAF6 and mitogen-activated protein kinase signaling adaptors (i.e., Erk, Jnk, p38, and Akt) in RANKL+ T cells. We conclude that SOCS3 plays a critical role in modulating cytokine signaling involved in RANKL-mediated DC-derived osteoclastogenesis during immune interactions with T cells and diabetes-associated severe inflammation-induced alveolar bone loss. Therefore, the development of SOCS3 inhibitors may have therapeutic potential as the target to halt inflammation-induced bone loss under pathological conditions in vivo.

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Ly6C defines a subset of memory-like CD27+ γδ T cells with inducible cancer-killing function

10.1101/2020.09.08.287854 ◽

2020 ◽

Author(s):

Robert Wiesheu ◽

Sarah C. Edwards ◽

Ann Hedley ◽

Kristina Kirschner ◽

Marie Tosolini ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cell ◽

Ex Vivo ◽

Phenotypic Diversity ◽

Critical Role ◽

Γδ T Cells ◽

Tumour Immunity ◽

Cytotoxic Molecules ◽

Killing Function

ABSTRACTIn mice, IFNγ-producing γδ T cells that express the co-stimulatory molecule, CD27, play a critical role in host defence and anti-tumour immunity. However, their phenotypic diversity, composition in peripheral and secondary lymphoid organs, similarity to αβ T cells as well as homology with human γδ T cells is poorly understood. Here, using single cell RNA sequencing, we show that CD27+ γδ T cells consist of two major clusters, which are distinguished by expression of Ly6C. We demonstrate that CD27+Ly6C— γδ T cells exhibit a naïve T cell-like phenotype, whereas CD27+Ly6C+ γδ T cells display a memory-like phenotype, produce several NK cell-related and cytotoxic molecules and are highly similar to both mouse CD8+ T cells and mature human γδ T cells. In a breast cancer mouse model, depletion of CD27+ γδ T cells failed to affect tumour growth, but these cells could be coerced into killing cancer cells after expansion ex vivo. These results identify novel subsets of γδ T cells in mice that are comparable to human γδ T cells, opening new opportunities for γδ T cell-based cancer immunotherapy research.

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