Dietary supplementation with purified citrus limonin glucoside does not alter ex vivo functions of circulating T lymphocytes or monocytes in overweight/obese human adults

In colorectal cancer (CRC), a high density of T lymphocytes represents a strong prognostic marker in subtypes of CRC. Optimized immunotherapy strategies to boost this T-cell response are still needed. A good candidate is the inflammasome pathway, an emerging player in cancer immunology that bridges innate and adaptive immunity. Its effector protein caspase-1 matures IL-18 that can promote a T-helper/cytotoxic (Th1/Tc1) response. It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model. We show that, in the majority of CRCs, tumor cells display an activated and functional caspase-1/IL-18 axis that contributes to drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα. Furthermore, unsupervised clustering identified three clusters of CRCs according to the caspase-1/IL-18/TIL density/interferon gamma (IFNγ) axis and microsatellite status. Together, our results strongly suggest that targeting the caspase-1/IL-18 axis can improve the anti-tumor immune response in subgroups of CRC.

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Generation and ex vivo expansion of cytotoxic T lymphocytes directed toward different types of leukemia or myelodysplastic cells using both HLA-matched and partially matched donors

Experimental Hematology ◽

10.1016/s0301-472x(03)00230-3 ◽

2003 ◽

Vol 31 (11) ◽

pp. 1031-1038 ◽

Cited By ~ 19

Author(s):

Daniela Montagna ◽

Rita Maccario ◽

Enrica Montini ◽

Roberto Tonelli ◽

Daniela Lisini ◽

...

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Ex Vivo ◽

Ex Vivo Expansion ◽

Different Types

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Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00273.2013 ◽

2014 ◽

Vol 307 (1) ◽

pp. L62-L70 ◽

Cited By ~ 11

Author(s):

Mark T. Kearns ◽

Lea Barthel ◽

Joseph M. Bednarek ◽

Zulma X. Yunt ◽

Peter M. Henson ◽

...

Keyword(s):

T Lymphocytes ◽

Alveolar Macrophage ◽

Fas Ligand ◽

Ex Vivo ◽

Pulmonary Inflammation ◽

Death Receptor ◽

Dependent Manner ◽

Resolution Of Inflammation ◽

Macrophage Apoptosis ◽

Rag 1

Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1−/−) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasL-dependent manner. Specifically, FasL-expressing CD8+T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8+T lymphocytes in the resolution of acute pulmonary inflammation.

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Vγ9Vδ2 T cells as a promising innovative tool for immunotherapy of hematologic malignancies

Oncology Reviews ◽

10.4081/oncol.2010.211 ◽

2011 ◽

Vol 4 (4) ◽

pp. 211

Author(s):

Serena Meraviglia ◽

Carmela La Mendola ◽

Valentina Orlando ◽

Francesco Scarpa ◽

Giuseppe Cicero ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Ex Vivo ◽

Γδ T Cells ◽

Hematologic Malignancies ◽

Cytolytic Activity ◽

Cell Therapies ◽

Stressed Cells

The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with hematologic malignancies.<br />

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Feasibility and safety of adoptive immunotherapy with ex vivo-generated autologous, cytotoxic T lymphocytes in patients with solid tumor

Cytotherapy ◽

10.3109/14653249.2011.610303 ◽

2012 ◽

Vol 14 (1) ◽

pp. 80-90 ◽

Cited By ~ 21

Author(s):

Daniela Montagna ◽

Ilaria Turin ◽

Roberta Schiavo ◽

Enrica Montini ◽

Nadia Zaffaroni ◽

...

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Adoptive Immunotherapy ◽

Solid Tumor ◽

Ex Vivo

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Immunological evaluation of ex vivo expanded umbilical cord blood T lymphocytes

Korean Journal of Gynecologic Oncology ◽

10.3802/kjgo.2006.17.1.74 ◽

2006 ◽

Vol 17 (1) ◽

pp. 74

Author(s):

Ji Youn Chung ◽

Young Man Kim ◽

Joo Hyun Nam

Keyword(s):

T Lymphocytes ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Ex Vivo ◽

Immunological Evaluation

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Modulation of the Effects of Lung Immune Response on Bone Marrow by Oral Antigen Exposure

BioMed Research International ◽

10.1155/2013/474132 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

P. Xavier-Elsas ◽

C. L. C. A. Silva ◽

L. Pinto ◽

T. Queto ◽

B. M. Vieira ◽

...

Keyword(s):

Bone Marrow ◽

T Lymphocytes ◽

Ex Vivo ◽

Allergen Challenge ◽

Allergic Airway Inflammation ◽

Oral Exposure ◽

Wild Type ◽

Homologous Antigen ◽

Mutant Strains

Allergic airway inflammation is attenuated by oral tolerization (oral exposure to allergen, followed by conventional sensitization and challenge with homologous antigen), which decreases airway allergen challenge-induced eosinophilic infiltration of the lungs and bone marrow eosinophilia. We examined its effects on bone marrow eosinophil and neutrophil production. Mice of wild type (BP-2, BALB/c, and C57BL/6) and mutant strains (lacking iNOS or CD95L) were given ovalbumin (OVA) or water (vehicle) orally and subsequently sensitized and challenged with OVA (OVA/OVA/OVA and H2O/OVA/OVA groups, resp.). Anti-OVA IgG and IgE, bone marrow eosinophil and neutrophil numbers, and eosinophil and neutrophil production ex vivo were evaluated. T lymphocytes from OVA/OVA/OVA or control H2O/OVA/OVA donors were transferred into naïve syngeneic recipients, which were subsequently sensitized/challenged with OVA. Alternatively, T lymphocytes were cocultured with bone marrow eosinophil precursors from histocompatible sensitized/challenged mice. OVA/OVA/OVA mice of the BP-2 and BALB/c strains showed, relative to H2O/OVA/OVA controls, significantly decreased bone marrow eosinophil counts and ex vivo eosinopoiesis/neutropoiesis. Full effectiveness in vivo required sequential oral/subcutaneous/intranasal exposures to the same allergen. Transfer of splenic T lymphocytes from OVA/OVA/OVA donors to naive recipients prevented bone marrow eosinophilia and eosinopoiesis in response to recipient sensitization/challenge and supressed eosinopoiesis upon coculture with syngeneic bone marrow precursors from sensitized/challenged donors.

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High Frequency of Skin-homing Melanocyte-specific Cytotoxic T Lymphocytes in Autoimmune Vitiligo

Journal of Experimental Medicine ◽

10.1084/jem.188.6.1203 ◽

1998 ◽

Vol 188 (6) ◽

pp. 1203-1208 ◽

Cited By ~ 285

Author(s):

Graham S. Ogg ◽

P. Rod Dunbar ◽

Pedro Romero ◽

Ji-Li Chen ◽

Vincenzo Cerundolo

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Ex Vivo ◽

Hla Class I ◽

Peripheral Tolerance ◽

Skin Homing ◽

Autoimmune Vitiligo ◽

Destruction Of Melanocytes

Vitiligo is an autoimmune condition characterized by loss of epidermal melanocytes. Using tetrameric complexes of human histocompatibility leukocyte antigen (HLA) class I to identify antigen-specific T cells ex vivo, we observed high frequencies of circulating MelanA-specific, A*0201-restricted cytotoxic T lymphocytes (A2–MelanA tetramer+ CTLs) in seven of nine HLA-A*0201–positive individuals with vitiligo. Isolated A2–MelanA tetramer+ CTLs were able to lyse A*0201-matched melanoma cells in vitro and their frequency ex vivo correlated with extent of disease. In contrast, no A2–MelanA tetramer+ CTL could be identified ex vivo in all four A*0201-negative vitiligo patients or five of six A*0201-positive asymptomatic controls. Finally, we observed that the A2–MelanA tetramer+ CTLs isolated from vitiligo patients expressed high levels of the skin homing receptor, cutaneous lymphocyte-associated antigen, which was absent from the CTLs seen in the single A*0201-positive normal control. These data are consistent with a role of skin-homing autoreactive melanocyte-specific CTLs in causing the destruction of melanocytes seen in autoimmune vitiligo. Lack of homing receptors on the surface of autoreactive CTLs could be a mechanism to control peripheral tolerance in vivo.

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561 ENHANCING RADIATION-INDUCED IMMUNOGENICITY IN THE MULTIMODAL TREATMENT OF ESOPHAGEAL CANCER: IS HYPOFRACTIONATION THE ANSWER?

Diseases of the Esophagus ◽

10.1093/dote/doaa087.146 ◽

2020 ◽

Vol 33 (Supplement_1) ◽

Author(s):

N Donlon ◽

M Davern ◽

A Sheppard ◽

J Elliott ◽

N Ravi ◽

...

Keyword(s):

Esophageal Cancer ◽

T Lymphocytes ◽

Cell Viability ◽

Cancer Cell ◽

Immune Checkpoint ◽

Multimodal Treatment ◽

Ex Vivo ◽

Tumour Response ◽

Immune Checkpoints ◽

Immune Checkpoint Blockers

Abstract Esophageal adenocarcinoma (EAC) is increasing exponentially year on year in Western civilisation, linked epidemiologically to GERD and obesity. It is characterized by a highly immunosuppressive tumour microenvironment (TME) and evasion of immune surveillance. A novel treatment option is upregulating immune mediated anti-tumour response via Immune Checkpoint Blockers (ICB). Methods The effects of immune checkpoint blockers were characterised in terms of proliferation, cytolysis and cancer cell viability. The basal expression of immune checkpoints (TIGIT, PD-1, PD-L1, PD-L2) and Damage Associated Molecular Patterns (Calreticulin, HMGB1) in EAC patients was profiled ex vivo using fresh tumor, blood and lymph-node tissue (n = 10) by flow cytometry. In an in-vitro study, T-lymphocytes were isolated and treated with Nivolumab, Pembrolizumab or Atezolizumab, activated and co-cultured for 48 hours with a panel of four esophageal cancer cell lines; OE33P, OE33R, FLO-1, FLO-1LM treated with 1.8Gy and 3.6Gy of radiation (Fig 1). Cytolysis was measured using a CCK8 assay.(n = 6). Results The expression of TIGIT, TIM-3, PD-1 and its ligands (PD-L1, PD-L2) were higher (p < 0.001) in EAC patients compared to age matched healthy controls. Similarly, when mimicking conditions of the TME including nutrient deprivation and hypoxia, this results in a significant (p < 0.001) increase in DAMP and ICB expression on CD3,4 and CD8 T cells in the TME when treated with radiation. T-lymphocytes induced by checkpoint blockers plus ionising radiation directly to the tumor resulted in the best repression of tumour growth with 3.6Gy inducing the highest rate of cytolysis (p < 0.001). ICB and radiation resulted in reduced cancer cell viability and proliferation. Conclusion Fractionated radiation can enhance immunologic function. In combination with ICB, this symbiotic relationship enhances the cytotoxic potential of T lymphocytes with conventional dosing, however, with hypofractionation, this signifies true immunogenicity, and as such this provides a basis for advocating for potential combination strategies with ICB in the multimodal treatment of EAC.

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