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1.
Cells ; 10(3)2021 03 03.
Article in English | MEDLINE | ID: mdl-33802622

ABSTRACT

Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.


Subject(s)
B7-H1 Antigen/genetics , Hepacivirus/immunology , Hepatitis C, Chronic/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Programmed Cell Death 1 Receptor/genetics , Receptors, Antigen, T-Cell, gamma-delta/genetics , Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Gene Expression Regulation , Hepacivirus/pathogenicity , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/virology , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Cellular/drug effects , Interleukins/genetics , Interleukins/immunology , Interleukins/therapeutic use , Lymphocyte Activation/drug effects , Precursor Cells, T-Lymphoid/drug effects , Precursor Cells, T-Lymphoid/immunology , Precursor Cells, T-Lymphoid/virology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Receptors, Antigen, T-Cell, gamma-delta/agonists , Receptors, Antigen, T-Cell, gamma-delta/immunology , Signal Transduction
2.
Cancer Res ; 70(24): 10024-7, 2010 Dec 15.
Article in English | MEDLINE | ID: mdl-21159627

ABSTRACT

Abundant interferon-γ secretion, potent cytotoxicity, and major histocompatibility complex-independent targeting of a large spectrum of tumors make γδ T cells attractive mediators of cancer immunotherapy. However, a better understanding of the molecular mechanisms involved in tumor cell recognition and γδ T-cell activation is required to improve the limited success of γδ T-cell-mediated treatments. Here, we review key advances in basic knowledge made over the past 3 years, and summarize the results of γδ T-cell-based clinical trials concluded to date. We also highlight new research directions on the basis of the modulation of receptors that control the function of γδ T cells.


Subject(s)
Immunotherapy, Adoptive/methods , Neoplasms/immunology , Neoplasms/therapy , Receptors, Antigen, T-Cell, gamma-delta/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Humans , Lymphocyte Activation , Receptors, Antigen, T-Cell, gamma-delta/agonists
3.
Curr Cancer Drug Targets ; 10(1): 27-36, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20088797

ABSTRACT

The broad antimicrobial and antitumoral reactivity of Vgamma9Vdelta2 T cells, their ability to produce inflammatory cytokines involved in protective immunity against intracellular pathogens and tumors and their strong cytolytic and bactericidal activities suggest their direct involvement in immune control of cancers and infections. gammadelta T cells can be selectively activated by naturally occurring or synthetic phosphoantigens, and drugs that enhance their accumulation into stressed cells, offering new avenues for the development of gammadelta T cell-based immunotherapies. The recent development of small drugs selectively activating Vgamma9Vdelta2 T lymphocytes, which upregulate endogenous phosphoantigens, has enabled investigators to design experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen-activated Vgamma9Vdelta2 T lymphocytes in humans. In this review, we focus on the recent advances of the activation/expansion of gammadelta 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 different types of cancer.


Subject(s)
Antigens/immunology , Diphosphonates/pharmacology , Immunotherapy, Adoptive/methods , Neoplasms/therapy , Receptors, Antigen, T-Cell, gamma-delta/agonists , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/transplantation , Animals , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Female , Humans , Lymphocyte Activation , Male , Mice , Neoplasms/immunology , T-Lymphocyte Subsets/immunology
4.
J Org Chem ; 73(4): 1365-70, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18211084

ABSTRACT

(E)-1-Hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) is an intermediate in the non-mevalonate pathway for the biosynthesis of isoprenoids and also serves as a very strong activator of human gamma delta T cells expressing Vgamma9Vdelta2 receptors. This paper describes the synthesis of analogues of HMBPP, in which the diphosphate group is replaced by potential isosteric moieties, i.e., carbamate, N-acyl-N'-oxy sulfamate, or aminosulfonyl carbamate functionalities. The potential of the synthesized analogues to stimulate Vgamma9/Vdelta2 T cell response or to inhibit GcpE and LytB, the last enzymes in the non-mevalonate pathway, was assessed.


Subject(s)
Phosphates/pharmacology , Receptors, Antigen, T-Cell, gamma-delta/agonists , Humans , Magnetic Resonance Spectroscopy , Phosphates/chemical synthesis , Spectrometry, Mass, Electrospray Ionization
5.
Crit Rev Immunol ; 28(5): 377-402, 2008.
Article in English | MEDLINE | ID: mdl-19166386

ABSTRACT

Many pharmaceutical drugs arc isolated from plants used in traditional medicines, and new plant-derived pharmaceutical drugs continue to be identified. Relevant to this review, different plant-derived agonists for gammadelta T cells are described that impart effector functions upon distinct subsets of these cells. Recently, plant tannins have been defined as one class of gammadelta T cell agonist and appear to preferentially activate the mucosal population. Mucosal gammadelta T cells function to modulate tissue immune responses and induce epithelium repair. Select tannins, isolated from apple peel, rapidly induce immune gene transcription in gammadelta T cells, leading to cytokinc production and increased responsiveness to secondary signals. Activity of these tannin preparations tracks to the procyanidin fraction, with the procyanidin trimer (C1) having the most robust activity defined to date. The response to the procyanidins is evolutionarily conserved in that responses are seen with human, bovine, and murine gammadelta T cells, although human cells show less selectivity. Procyanidin-induced responses described in this review likely account for the expansion of mucosal gammadelta T cells seen in mice and rats fed soluble extracts of tannins. Use of procyanidins to activate gammadelta T cells may represent a novel approach for the treatment of tissue damage and autoimmune diseases.


Subject(s)
Plant Preparations/pharmacology , Receptors, Antigen, T-Cell, gamma-delta/agonists , T-Lymphocytes/drug effects , Tannins/pharmacology , Animals , Chromatography, High Pressure Liquid , Flavonoids/pharmacology , Herbal Medicine , Humans , Phenols/pharmacology , Plants, Medicinal , Polyphenols , Proanthocyanidins/isolation & purification , Proanthocyanidins/pharmacology , Receptors, Antigen, T-Cell, gamma-delta/analysis , T-Lymphocytes/immunology , Tannins/isolation & purification
6.
J Immunol ; 179(10): 6468-78, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17982035

ABSTRACT

Gammadelta T cells are innate immune cells that participate in host responses against many pathogens and cancers. Recently, phosphoantigen-based drugs, capable of expanding gammadelta T cells in vivo, entered clinical trials with the goal of enhancing innate immune system functions. Potential shortcomings of these drugs include the induction of nonresponsiveness upon repeated use and the expansion of only the Vdelta2 subset of human gammadelta T cells. Vdelta1 T cells, the major tissue subset, are unaffected by phosphoantigen agonists. Using FACS-based assays, we screened primary bovine cells for novel gammadelta T cell agonists with activities not encompassed by the current treatments in an effort to realize the full therapeutic potential of gammadelta T cells. We identified gammadelta T cell agonists derived from the condensed tannin fractions of Uncaria tomentosa (Cat's Claw) and Malus domestica (apple). Based on superior potency, the apple extract was selected for detailed analyses on human cells. The apple extract was a potent agonist for both human Vdelta1 and Vdelta2 T cells and NK cells. Additionally, the extract greatly enhanced phosphoantigen-induced gammadelta T cell expansion. Our analyses suggest that a tannin-based drug may complement the phosphoantigen-based drugs, thereby enhancing the therapeutic potential of gammadelta T cells.


Subject(s)
Cat's Claw , Cell Division/drug effects , Fruit , Interleukin-2 Receptor alpha Subunit/immunology , Malus , Plant Extracts/pharmacology , Receptors, Antigen, T-Cell, gamma-delta/agonists , Tannins/pharmacokinetics , Up-Regulation/drug effects , Animals , Cat's Claw/chemistry , Cattle , Fruit/chemistry , Humans , Interleukin-2 Receptor alpha Subunit/biosynthesis , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Malus/chemistry , Neoplasms/drug therapy , Neoplasms/immunology , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocytes , Tannins/chemistry , Tannins/therapeutic use
7.
J Immunol ; 177(9): 6038-43, 2006 Nov 01.
Article in English | MEDLINE | ID: mdl-17056529

ABSTRACT

During thymus development, immature T cells become committed to two distinct lineages based upon expression of alphabeta or gammadelta TCR. In the alphabeta lineage, developing thymocytes progressively extinguish transcription of the TCRgamma genes by a poorly understood process known as gamma silencing. We show that alphabeta lineage thymocytes in mice lacking a functional pre-TCR undergo limited proliferation and fail to silence TCRgamma genes during development. Stimulation of pre-TCR-deficient immature thymocytes with anti-CD3 Abs does not directly down-regulate TCRgamma transcription but restores TCRgamma silencing following proliferation. Collectively our data reveal an important role for pre-TCR induced proliferation in activating the TCRgamma silencer in alphabeta lineage thymocytes, a process that may reinforce alphabeta or gammadelta lineage commitment.


Subject(s)
Gene Silencing , Receptors, Antigen, T-Cell, alpha-beta/analysis , Receptors, Antigen, T-Cell, gamma-delta/genetics , T-Lymphocyte Subsets/immunology , Thymus Gland/growth & development , Animals , Antibodies/pharmacology , CD3 Complex/immunology , Cell Lineage/genetics , Cell Proliferation , Mice , Receptors, Antigen, T-Cell, alpha-beta/agonists , Receptors, Antigen, T-Cell, gamma-delta/agonists , Silencer Elements, Transcriptional/genetics , T-Lymphocyte Subsets/drug effects , Thymus Gland/cytology , Thymus Gland/immunology
8.
J Med Chem ; 48(8): 2957-63, 2005 Apr 21.
Article in English | MEDLINE | ID: mdl-15828834

ABSTRACT

We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Bone Resorption/drug therapy , Diphosphonates/chemical synthesis , Pyridinium Compounds/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bone Resorption/metabolism , Calcium/metabolism , Dictyostelium/drug effects , Dictyostelium/enzymology , Diphosphonates/chemistry , Diphosphonates/pharmacology , Geranyltranstransferase , Humans , In Vitro Techniques , Leishmania major/enzymology , Metatarsal Bones/drug effects , Metatarsal Bones/metabolism , Mice , Models, Molecular , Pyridinium Compounds/chemistry , Pyridinium Compounds/pharmacology , Quantitative Structure-Activity Relationship , Receptors, Antigen, T-Cell, gamma-delta/agonists , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology
9.
J Immunol ; 174(3): 1338-47, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15661891

ABSTRACT

Metastatic renal cell carcinoma, inherently resistant to conventional treatments, is considered immunogenic. Indeed, partial responses are obtained after treatment with cytokines such as IL-2 or IFN-alpha, suggesting that the immune system may control the tumor growth. In this study, we have investigated the ability of the main subset of peripheral gammadelta lymphocytes, the Vgamma9Vdelta2-TCR T lymphocytes, to induce an effective cytotoxic response against autologous primary renal cell carcinoma lines. These gammadelta T cells were expanded ex vivo using a Vgamma9Vdelta2 agonist, a synthetic phosphoantigen called Phosphostim. From 11 of 15 patients, the peripheral Vgamma9Vdelta2 T cells were amplified in vitro by stimulating PBMCs with IL-2 and Phosphostim molecule. These expanded Vgamma9Vdelta2 T cells express activation markers and exhibit an effector/memory phenotype. They display a selective lytic potential toward autologous primary renal tumor cells and not against renal NC. The lytic activity involves the perforin-granzyme pathway and is mainly TCR and NKG2D receptor dependent. Furthermore, an increased expression of MHC class I-related molecule A or B proteins, known ligands of NKG2D, are detected on primary renal tumor cells. Interestingly, from 2 of the 11 positive cultures in response to Phosphostim, expanded-Vgamma9Vdelta2 T cells present an expression of killer cell Ig-like receptors, suggesting their prior recruitment in vivo. Unexpectedly, on serial frozen sections from three tumors, we observe a gammadelta lymphocyte infiltrate that was mainly composed of Vgamma9Vdelta2 T cells. These results outline that Vgamma9Vdelta2-TCR effectors may represent a promising approach for the treatment of metastatic renal cell carcinoma.


Subject(s)
Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Cytotoxicity, Immunologic , Diphosphates/immunology , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Receptors, Antigen, T-Cell, gamma-delta/physiology , T-Lymphocyte Subsets/immunology , Adult , Aged , Aged, 80 and over , Antigens/immunology , Antigens/pharmacology , Carcinoma, Renal Cell/secondary , Cell Differentiation/immunology , Cell Line, Tumor , Diphosphates/pharmacology , Female , Humans , Immunophenotyping , Kidney Neoplasms/therapy , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/pathology , Lymphocyte Activation/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/pathology , Male , Middle Aged , NK Cell Lectin-Like Receptor Subfamily K , Receptors, Antigen, T-Cell, gamma-delta/agonists , Receptors, Antigen, T-Cell, gamma-delta/biosynthesis , Receptors, Immunologic/biosynthesis , Receptors, Immunologic/metabolism , Receptors, Immunologic/physiology , Receptors, KIR , Receptors, Natural Killer Cell , T-Lymphocyte Subsets/metabolism
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