RESUMO
Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address these challenges, we previously developed a switchable CAR (sCAR) T cell system that allows fully tunable, on/off control over engineered cellular activity. To further evaluate the platform, we generated and assessed different murine sCAR constructs to determine the factors that afford efficacy, persistence, and expansion of sCAR T cells in a competent immune system. We find that sCAR T cells undergo significant in vivo expansion, which is correlated with potent antitumor efficacy. Most importantly, we show that the switch dosing regimen not only allows control over B cell populations through iterative depletion and repopulation, but that the "rest" period between dosing cycles is the key for induction of memory and expansion of sCAR T cells. These findings introduce rest as a paradigm in enhancing memory and improving the efficacy and persistence of engineered T cell products.
Assuntos
Bioengenharia/métodos , Imunoterapia Adotiva/métodos , Animais , Antígenos CD19/imunologia , Linfócitos B/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica/imunologia , Feminino , Região de Troca de Imunoglobulinas/genética , Região de Troca de Imunoglobulinas/imunologia , Ativação Linfocitária/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Modelos Biológicos , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologiaRESUMO
Commensal microorganisms colonize barrier surfaces of all multicellular organisms, including those of humans. For more than 500 million years, commensal microorganisms and their hosts have coevolved and adapted to each other. As a result, the commensal microbiota affects many immune and nonimmune functions of their hosts, and de facto the two together comprise one metaorganism. The commensal microbiota communicates with the host via biologically active molecules. Recently, it has been reported that microbial imbalance may play a critical role in the development of multiple diseases, such as cancer, autoimmune conditions, and increased susceptibility to infection. In this review, we focus on the role of the commensal microbiota in the development, progression, and immune evasion of cancer, as well as some modulatory effects on the treatment of cancer. In particular, we discuss the mechanisms of microbiota-mediated regulation of innate and adaptive immune responses to tumors, and the consequences on cancer progression and whether tumors subsequently become resistant or susceptible to different anticancer therapeutic regiments.
Assuntos
Doenças Autoimunes/microbiologia , Carcinogênese/imunologia , Microbiota/imunologia , Neoplasias/microbiologia , Imunidade Adaptativa , Animais , Antineoplásicos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Evolução Biológica , Carcinogênese/patologia , Humanos , Imunidade Inata , Imunomodulação , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Metagenoma/imunologia , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Simbiose/imunologia , Evasão TumoralRESUMO
Exosomes are nanometric membrane vesicles of late endosomal origin released by most, if not all, cell types as a means of sophisticated intercellular communication. A multitude of studies showed how exosomes can mediate and regulate immune responses against tumors. Dendritic cell-derived exosomes (Dex) have received much attention as immunotherapeutic anticancer agents since the discovery that they harbor functional MHC-peptide complexes, in addition to various other immune-stimulating components, that together facilitate immune cell-dependent tumor rejection. The therapeutic potential of Dex has been substantiated with their development and clinical testing in the treatment of cancer. This review focuses on mechanisms by which Dex interact with and influence immune cells and describes how they can be engineered to promote their immunogenic capacity as novel and dynamic anticancer agents.
Assuntos
Células Dendríticas/citologia , Células Dendríticas/imunologia , Exossomos/imunologia , Imunoterapia/métodos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto/métodos , Células Dendríticas/patologia , Modelos Animais de Doenças , Exossomos/genética , Exossomos/patologia , Humanos , Camundongos , Terapia de Alvo Molecular/métodos , Neoplasias Experimentais/patologia , Células Tumorais CultivadasRESUMO
Current Food and Drug Administration (FDA)-approved CD19-specific chimeric antigen receptor (CAR) T-cell therapies for B-cell malignancies are constitutively active and while efficacious, can cause morbidity and mortality. Their toxicities might be reduced if CAR T-cell activity was regulatable rather than constitutive. To test this, we compared the efficacies and morbidities of constitutively active (conventional) and regulatable (switchable) CAR (sCAR) T-cells specific for human CD19 (huCD19) in an immune-competent huCD19+ transgenic mouse model.Conventional CAR (CAR19) and sCAR T-cells were generated by retrovirally transducing C57BL/6 (B6) congenic T-cells with constructs encoding antibody-derived single chain Fv (sFv) fragments specific for huCD19 or a peptide neoepitope (PNE), respectively. Transduced T-cells were adoptively transferred into huCD19 transgenic hemizygous (huCD19Tg/0 ) B6 mice; healthy B-cells in these mice expressed huCD19Tg Prior to transfer, recipients were treated with a lymphodepleting dose of cyclophosphamide to enhance T-cell engraftment. In tumor therapy experiments, CAR19 or sCAR T-cells were adoptively transferred into huCD19Tg/0 mice bearing a syngeneic B-cell lymphoma engineered to express huCD19. To regulate sCAR T cell function, a switch protein was generated that contained the sCAR-specific PNE genetically fused to an anti-huCD19 Fab fragment. Recipients of sCAR T-cells were injected with the switch to link sCAR effector with huCD19+ target cells. Mice were monitored for survival, tumor burden (where appropriate), morbidity (as measured by weight loss and clinical scores), and peripheral blood lymphocyte frequency.CAR19 and sCAR T-cells functioned comparably regarding in vivo expansion and B-cell depletion. However, sCAR T-cells were better tolerated as evidenced by the recipients' enhanced survival, reduced weight loss, and improved clinical scores. Discontinuing switch administration allowed healthy B-cell frequencies to return to pretreatment levels.In our mouse model, sCAR T-cells killed huCD19+ healthy and malignant B-cells and were better tolerated than CAR19 cells. Our data suggest sCAR might be clinically superior to the current FDA-approved therapies for B-cell lymphomas due to the reduced acute and chronic morbidities and mortality, lower incidence and severity of side effects, and B-cell reconstitution on cessation of switch administration.
Assuntos
Antígenos CD19 , Linfoma de Células B , Estados Unidos , Humanos , Camundongos , Animais , Camundongos Endogâmicos C57BL , Linfócitos T , Linfoma de Células B/terapia , Modelos Animais de Doenças , Camundongos Transgênicos , Morbidade , Redução de PesoRESUMO
A unique class of IFN-producing killer dendritic cells (IKDC) resembling natural killer cells has been defined that can recognize and lyse tumor cells through a tumor necrosis factor-related apoptosis-inducing ligand-dependent mechanism. IKDC may mediate the host-dependent antitumor activity of Gleevec/STI571 and other therapeutics that can inhibit the c-kit tyrosine kinase. IKDC represent an important new component of the innate immune system responding to cancer.
Assuntos
Células Dendríticas/imunologia , Interferon gama/imunologia , Neoplasias Experimentais/imunologia , Animais , Antineoplásicos/farmacologia , Benzamidas , Células Dendríticas/efeitos dos fármacos , Mesilato de Imatinib , Imunoterapia/métodos , Interferon gama/biossíntese , Camundongos , Neoplasias Experimentais/terapia , Piperazinas/farmacologia , Pirimidinas/farmacologiaRESUMO
Immune checkpoint inhibitors (CPIs) are associated with a number of immune-related adverse events and low response rates. We provide preclinical evidence for use of a retroviral replicating vector (RRV) selective to cancer cells, to deliver CPI agents that may circumvent such issues and increase efficacy. An RRV, RRV-scFv-PDL1, encoding a secreted single chain variable fragment targeting PD-L1 can effectively compete with PD-1 for PD-L1 occupancy. Cell binding assays showed trans-binding activity on 100% of cells in culture when infection was limited to 5% RRV-scFv-PDL1 infected tumor cells. Further, the ability of scFv PD-L1 to rescue PD-1/PD-L1 mediated immune suppression was demonstrated in a co-culture system consisting of human-derived immune cells and further demonstrated in several syngeneic mouse models including an intracranial tumor model. These tumor models showed that tumors infected with RRV-scFv-PD-L1 conferred robust and durable immune-mediated anti-tumor activity comparable or superior to systemically administered anti-PD-1 or anti PD-L1 monoclonal antibodies. Importantly, the nominal level of scFv-PD-L1 detected in serum is â¼50-150 fold less than reported for systemically administered therapeutic antibodies targeting immune checkpoints. These results support the concept that RRV-scFv-PDL1 CPI strategy may provide an improved safety and efficacy profile compared to systemic monoclonal antibodies of currently approved therapies.
RESUMO
Exosomes are nanometer-sized membrane vesicles invaginating from multivesicular bodies and secreted from different cell types. They represent an "in vitro" discovery, but vesicles with the hallmarks of exosomes are present in vivo in germinal centers and biological fluids. Their protein and lipid composition is unique and could account for their expanding functions such as eradication of obsolete proteins, antigen presentation, or "Trojan horses" for viruses or prions. The potential of dendritic cell-derived exosomes (Dex) as cell-free cancer vaccines is addressed in this review. Lessons learned from the pioneering clinical trials allowed reassessment of the priming capacities of Dex in preclinical models, optimizing clinical protocols, and delineating novel, biological features of Dex in cancer patients.
Assuntos
Vacinas Anticâncer/imunologia , Endossomos/imunologia , Neoplasias/tratamento farmacológico , Animais , Vacinas Anticâncer/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Endossomos/química , Endossomos/metabolismo , Humanos , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Aneuploidy and chromosomal instability, which are frequent in cancer, can result from the asymmetric division of tetraploid precursors. Genomic instability may favor the generation of more aggressive tumor cells with a reduced propensity for undergoing apoptosis. To assess the impact of tetraploidization on apoptosis regulation, we generated a series of stable tetraploid HCT116 and RKO colon carcinoma cell lines. When comparing diploid parental cells with tetraploid clones, we found that such cells were equally sensitive to a series of cytotoxic agents (staurosporine [STS], hydroxyurea, etoposide), as well as to the lysis by natural killer cells. In strict contrast, tetraploid cells were found to be relatively resistant against a series of DNA-damaging agents, namely cisplatin, oxaliplatin, camptothecin, and gamma- and UVC-irradiation. This increased resistance correlated with a reduced manifestation of apoptotic parameters (such as the dissipation of the mitochondrial transmembrane potential and the degradation of nuclear DNA) in tetraploid as compared to diploid cells subjected to DNA damage. Moreover, tetraploid cells manifested an enhanced baseline level of p53 activation. Inhibition of p53 abolished the difference in the susceptibility of diploid and tetraploid cancer cells to DNA damage-induced apoptosis. These data point to an intrinsic resistance of tetraploid cells against radiotherapy and DNA-targeted chemotherapy that may be linked to the status of the p53 system.
Assuntos
Apoptose , Neoplasias do Colo/patologia , Dano ao DNA , Poliploidia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Imunofluorescência , Humanos , Células Matadoras Naturais/imunologia , Raios UltravioletaRESUMO
Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.
RESUMO
Myeloid cells represent a major component of the tumor microenvironment, where they play divergent dual roles. They can induce antitumor immune responses, but mostly they promote immune evasion, tumor progression, and metastasis formation. Thus, strategies aiming at reprogramming the tumor microenvironment represent a promising immunotherapy approach. Myeloid cells respond to environmental factors including signals derived from commensal microbes. In this Cancer Immunology at the Crossroads overview, we discuss recent advances on the effects of the commensal microbiota on myeloid-cell functions and how they affect the response to cancer therapy.
Assuntos
Microbiota/imunologia , Células Mieloides/imunologia , Neoplasias/terapia , Animais , Diferenciação Celular/imunologia , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Neoplasias/imunologia , Neoplasias/microbiologia , Simbiose/imunologia , Microambiente Tumoral/imunologiaRESUMO
Changes in the interactions among the gut microbiota, intestinal epithelium, and host immune system are associated with many diseases, including cancer. We discuss how environmental factors infuence this cross-talk during oncogenesis and tumor progression and how manipulations of the gut microbiota might improve the clinical activity of anticancer agents.
Assuntos
Trato Gastrointestinal/microbiologia , Microbiota , Neoplasias/microbiologia , Antineoplásicos/uso terapêutico , Carcinogênese/patologia , Disbiose , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Cyclophosphamide, one of the most efficient tumoricidal, antiangiogenic, and immunostimulatory drugs employed to date mediates part of its effects through intestinal bacteria, against which the host becomes immunized during treatment. Our recent work suggests that anti-commensal effector pTH17 and memory TH1 CD4+ T-cell responses are indispensable for optimal anticancer effects as mediated by cyclophosphamide.
RESUMO
Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.
Assuntos
Antineoplásicos/uso terapêutico , Translocação Bacteriana/efeitos dos fármacos , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Intestino Delgado/microbiologia , Microbiota/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Transferência Adotiva , Animais , Antibacterianos/administração & dosagem , Vida Livre de Germes , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/fisiologia , Memória Imunológica , Tecido Linfoide/imunologia , Tecido Linfoide/microbiologia , Camundongos , Microbiota/efeitos dos fármacos , Células Th17/imunologia , Células Th17/transplanteRESUMO
During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1-dependent tumor progression in NK cell-controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit(-) (CD11b(-)) into Kit(+) natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit(+) NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit(+) NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1-dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18-binding protein dramatically reduced the accumulation of Kit(+)CD11b(-) NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit(+)CD11b(-) NK cells endowed with B7-H1-dependent immunoablative functions in mice.
Assuntos
Interleucina-18/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Animais , Antígeno B7-H1/análise , Antígeno B7-H1/fisiologia , Antígeno CD11b/análise , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-kit/análiseRESUMO
Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called "metronomic CTX") opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4(+) T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic "pro-immunogenic" activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Vacinas Anticâncer , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Antineoplásicos Alquilantes/farmacologia , Ciclofosfamida/farmacologia , Desenho de Fármacos , Humanos , Imunossupressores/farmacologiaRESUMO
Cyclin-dependent kinase (CDK) inhibitors have been considered as excellent drug candidates for cancer therapy owing to their potential capacity to restore cell cycle control. The first generation of CDK inhibitors showed modest clinical advantages that could be attributed to off-target effects preventing them from reaching therapeutic concentrations. A phase I dose-escalation study using the second generation multi-CDK inhibitor PHA-793887 was conducted on a total of 19 patients with advanced refractory malignancies in two sites in Europe: the University of Leeds and St. James's Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR). Fifteen patients were treated at IGR. Six among these patients manifested the reactivation of herpes virus replication. In vitro experiments revealed that PHA-793887 severely impaired signaling by toll-like receptors (such as TLR3, TLR4 and TLR9) in dendritic cells (DC), thus suppressing the production of multiple cytokines (type 1 interferon, interleukin-6,-10, -12, and tumor necrosis factorα) by mature DC, as well as the DC-stimulated production of interferon-γ by natural killer cells. Pharmacological inhibition of glycogen synthase-3ß (GSK-3ß), one of the off-targets of PHA-793887, did not cause such immunological defects. Altogether, these data underscore a hitherto unsuspected immunosuppressive effect of PHA-793887.
Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Infecções por Herpesviridae/induzido quimicamente , Neoplasias/tratamento farmacológico , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirróis/efeitos adversos , Pirróis/farmacologia , Receptores Toll-Like/antagonistas & inibidores , Adulto , Idoso , Células Cultivadas , Quinases Ciclina-Dependentes/metabolismo , Suscetibilidade a Doenças/induzido quimicamente , Suscetibilidade a Doenças/patologia , Feminino , Herpesviridae/efeitos dos fármacos , Herpesviridae/fisiologia , Infecções por Herpesviridae/patologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/patologia , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismoRESUMO
Low doses of the alkylating agent cyclophosphamide (CTX) mediate antiangiogenic and immunostimulatory effects, leading to potent tumoricidal activity in association with various immunotherapeutic strategies. Here, we show in rodents and cancer patients that CTX markedly promotes the differentiation of CD4(+) T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells. Because Th17 are potent inducers of tissue inflammation and autoimmunity, these results suggest impact on the clinical management of various types of malignancies treated with alkylating agents and a potential need to optimize CTX-based immunotherapy in patients.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Ciclofosfamida/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Células Th17/efeitos dos fármacos , Adulto , Idoso , Animais , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Diferenciação Celular/imunologia , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Mesilato de Imatinib , Interleucina-2/administração & dosagem , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/patologiaRESUMO
Dendritic cell-derived exosomes (Dex) are nanovesicles bearing major histocompatibility complexes promoting T-cell-dependent antitumor effects in mice. Two phase I clinical trials aimed at vaccinating cancer patients with peptide-pulsed Dex have shown the feasibility and safety of inoculating clinical-grade Dex, but have failed to show their immunizing capacity. These low immunogenic capacities have led us to develop second-generation Dex with enhanced immunostimulatory properties. Here, we show that interferon-γ is a key cytokine conditioning the dendritic cell to induce the expression of CD40, CD80, CD86, and CD54 on Dex, endowing them with direct and potent peptide-dependent CD8(+) T-cell-triggering potential in vitro and in vivo. In this study, we describe the clinical grade process to manufacture large-scale interferon-γ-Dex vaccines and their quality control parameters currently used in a phase II trial.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Células Dendríticas/imunologia , Exossomos/imunologia , Interferon gama/imunologia , Animais , Apresentação de Antígeno , Antígenos de Neoplasias/imunologia , Antígeno B7-1/genética , Antígeno B7-2/genética , Antígenos CD40 , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/metabolismo , Expressão Gênica , Humanos , Immunoblotting , Molécula 1 de Adesão Intercelular/genética , Ativação Linfocitária , Camundongos , Camundongos TransgênicosRESUMO
Immunosuppressive cytokines subvert innate and adaptive immune responses during cancer progression. The inflammatory cytokine interleukin-18 (IL-18) is known to accumulate in cancer patients, but its pathophysiological role remains unclear. In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1-dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is upregulated by IL-18. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18-binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models. Together, these results define IL-18 as an immunosuppressive cytokine in cancer. Our findings suggest novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18.
Assuntos
Antígenos de Superfície/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Interleucina-18/fisiologia , Melanoma Experimental/imunologia , Animais , Antígenos de Superfície/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Autoanticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Tolerância Imunológica , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica/imunologia , Receptor de Morte Celular Programada 1RESUMO
Exosomes are nanovesicles originating from late endosomal compartments and secreted by most living cells in ex vivo cell culture conditions. The interest in exosomes was rekindled when B-cell and dendritic cell-derived exosomes were shown to mediate MHC-dependent immune responses. Despite limited understanding of exosome biogenesis and physiological relevance, accumulating evidence points to their bioactivity culminating in clinical applications in cancer. This review focuses on the preclinical studies exploiting the immunogenicity of dendritic cell-derived exosomes (Dex) and will elaborate on the past and future vaccination trials conducted using Dex strategy in melanoma and non-small cell lung cancer patients.