RESUMEN
Glioblastoma is the most common and aggressive type of brain tumor with high recurrence and fatality rates. Although various therapeutic strategies have been explored, there is currently no effective treatment for glioblastoma. Recently, the number of immunotherapeutic strategies has been tested for malignant brain tumors. Invariant natural killer T (iNKT) cells play an important role in anti-tumor immunity. To address if iNKT cells can target glioblastoma to exert anti-tumor activity, we assessed the expression of CD1d, an antigen-presenting molecule for iNKT cells, on glioblastoma cells. Glioblastoma cells from 10 of 15 patients expressed CD1d, and CD1d-positive glioblastoma cells pulsed with glycolipid ligand induced iNKT cell-mediated cytotoxicity in vitro. Although CD1d expression was low on glioblastoma stem-like cells, retinoic acid, which is the most common differentiating agent, upregulated CD1d expression in these cells and induced iNKT cell-mediated cytotoxicity. Moreover, intracranial administration of human iNKT cells induced tumor regression of CD1d-positive glioblastoma in orthotopic xenografts in NOD/Shi-scid IL-2RγKO (NOG) mice. Thus, CD1d expression represents a novel target for NKT cell-based immunotherapy for glioblastoma patients.
Asunto(s)
Antígenos CD1d/metabolismo , Neoplasias Encefálicas/inmunología , Vacunas contra el Cáncer/inmunología , Glioblastoma/inmunología , Inmunoterapia Adoptiva/métodos , Células T Asesinas Naturales/metabolismo , Anciano , Animales , Presentación de Antígeno , Neoplasias Encefálicas/terapia , Células Cultivadas , Citotoxicidad Inmunológica , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/terapia , Humanos , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/trasplante , Trasplante de Neoplasias , Tretinoina/metabolismoRESUMEN
The role of immune checkpoint inhibitors in metastatic lung cancer has been established in recent years and the pretherapeutic profiles of the tumor microenvironment in responders have been increasingly reported. The role of salvage surgery and the immune profiles of the posttherapeutic specimens in patients achieving an objective response have rarely been studied. We report a case of metastatic lung cancer treated by anti-programmed death-1 Ab followed by surgical resection. The immune status of the tumor was assessed, showing germinal center formation, memory B cell infiltration, and a high frequency of interferon gamma -secreting T cells.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Receptor de Muerte Celular Programada 1/inmunología , Anciano , Linfocitos B/inmunología , Centro Germinal/inmunología , Humanos , Masculino , Linfocitos T/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vß11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d.
Asunto(s)
Antígenos CD1d/metabolismo , Leucemia/inmunología , Leucemia/metabolismo , Activación de Linfocitos/inmunología , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Animales , Antígenos CD1d/genética , Biomarcadores , Degranulación de la Célula , Línea Celular Tumoral , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Citocinas/metabolismo , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Femenino , Edición Génica , Xenoinjertos , Humanos , Inmunofenotipificación , Leucemia/genética , Leucemia/patología , Activación de Linfocitos/genética , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Gatillantes de la Citotoxidad Natural/metabolismoRESUMEN
Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line-derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL-12 and tumor necrosis factor (TNF)-α production from mature DC, while no effect of SH-SY5Y cell supernatant was noted. In addition, IL-6 and IL-10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. α-Galactosylceramide-pulsed DC co-cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)-γ after stimulation with neuroblastoma cell line supernatant-cultured DC was reversed by addition of IL-12. CD40 expression and IL-12 production in NLF-sup-treated DC were increased by addition of exogenous IFN-γ. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and αGalCer-pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN-γ production.
Asunto(s)
Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Neuroblastoma/inmunología , Antígenos CD1/inmunología , Línea Celular , Línea Celular Tumoral , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-12/inmunología , Interleucina-4/inmunología , Receptores de Lipopolisacáridos/inmunología , Monocitos/inmunología , Monocitos/metabolismoRESUMEN
Thymus-derived regulatory T cells (tTregs) play pivotal roles in immunological self-tolerance and homeostasis. A majority of tTregs are reactive to self-antigens and are constantly exposed to antigenic stimulation. Despite this continuous stimulation, tTreg and conventional T-cell populations remain balanced during homeostasis, but the mechanisms controlling this balance are unknown. We previously reported a form of activation-induced cell death, which is dependent on p53 (p53-induced CD28-dependent T-cell apoptosis, PICA). Under PICA-inducing conditions, tTregs survive while a majority of conventional T cells undergo apoptosis, suggesting there is a survival mechanism that protects tTregs. Here, we report that the expression of RasGRP1 (Ras guanyl-releasing protein 1) is required for PICA, as conventional T cells isolated from RasGRP1-deficient mice become resistant to PICA. After continuous stimulation, tTregs express a substantially lower amount of RasGRP1 compared to conventional T cells. This reduced expression of RasGRP1 is dependent on TGF-ß, as addition of TGF-ß to conventional T cells reduces RasGRP1 expression. Conversely, RasGRP1 expression in tTregs increases when TGF-ß signaling is inhibited. Together, these data show that RasGRP1 expression is repressed in tTregs by TGF-ß signaling and suggests that reduced RasGRP1 expression is critical for tTregs to resist apoptosis caused by continuous antigen exposure.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/metabolismo , Linfocitos T Reguladores/inmunología , Timo/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Apoptosis , Antígenos CD28/metabolismo , Diferenciación Celular , Células Cultivadas , Regulación de la Expresión Génica , Factores de Intercambio de Guanina Nucleótido/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor Cross-Talk , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Due to the strong tumoricidal activities of activated natural killer T (NKT) cells, invariant NKT cell-based immunotherapy has shown promising clinical efficacy. However, suppressive factors, such as regulatory T cells (Tregs), may be obstacles in the use of NKT cell-based cancer immunotherapy for advanced cancer patients. Here, we investigated the suppressive effects of Tregs on NKT cells and the underlying mechanisms with the aim to improve the antitumor activities of NKT cells. METHODS: Peripheral blood samples were obtained from healthy donors, patients with benign tumors, and patients with head and neck squamous cell carcinoma (HNSCC). NKT cells, induced with α-galactosylceramide (α-GalCer), and monocyte-derived dendritic cells (DCs) were co-cultured with naïve CD4+ T cell-derived Tregs to investigate the mechanism of the Treg suppressive effect on NKT cell cytotoxic function. The functions and phenotypes of NKT cells were evaluated with flow cytometry and cytometric bead array. RESULTS: Treg suppression on NKT cell function required cell-to-cell contact and was mediated via impaired DC maturation. NKT cells cultured under Treg-enriched conditions showed a decrease in CD4- NKT cell frequency, which exert strong tumoricidal responsiveness upon α-GalCer stimulation. The same results were observed in HNSCC patients with significantly increased effector Tregs. CONCLUSION: Tregs exert suppressive effects on NKT cell tumoricidal function by inducing more CD4- NKT cell anergy and less CD4+ NKT cell anergy. Both Treg depletion and NKT cell recovery from the anergy state may be important for improving the clinical efficacy of NKT cell-based immunotherapy in patients with advanced cancers.
Asunto(s)
Neoplasias de Cabeza y Cuello/inmunología , Células T Asesinas Naturales/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Linfocitos T Reguladores/inmunología , Anciano , Anciano de 80 o más Años , Células Cultivadas , Anergia Clonal , Citotoxicidad Inmunológica , Femenino , Humanos , Vigilancia Inmunológica , Terapia de Inmunosupresión , Masculino , Persona de Mediana EdadRESUMEN
Invariant natural killer T (iNKT) cells exhibit potent antitumor effects upon activation by recognizing a specific glycolipid antigen. We previously performed phase I-II clinical studies to utilize iNKT cells using α-galactosylceramide-pulsed dendritic cells and identified leukotriene B4 12-hydroxydehydrogenase (LTB4DH) as a biomarker highly expressed in T cells derived from non-small cell lung cancer (NSCLC) patients who showed prolonged survival in respond to the iNKT cell immunotherapy. Because LTB4DH expression correlated with prolonged survival of NSCLC patients, we considered LTB4DH to play a role in iNKT cell immunotherapy. We herein demonstrate that the overexpression of LTB4DH in CD4+ or CD8+ T cells increases interferon-γ production and tumoricidal activity in the presence of prostaglandin E2. Moreover, the expression of granzyme a, granzyme b, and perforin mRNA was increased in LTB4DH-overexpressing cells.
Asunto(s)
Oxidorreductasas de Alcohol/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Células Dendríticas/inmunología , Galactosilceramidas/farmacología , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/terapia , Oxidorreductasas de Alcohol/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/trasplante , Dinoprostona/inmunología , Dinoprostona/metabolismo , Granzimas/genética , Granzimas/inmunología , Humanos , Inmunoterapia/métodos , Interferón gamma/genética , Interferón gamma/inmunología , Células K562 , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/patología , Perforina/genética , Perforina/inmunología , Cultivo Primario de Células , ARN Mensajero/genética , ARN Mensajero/inmunología , Transducción de Señal , Análisis de SupervivenciaRESUMEN
BACKGROUND: Invariant natural killer T (iNKT) cells play an important role in tumor immunity, enhancing both innate and acquired immunity. We have previously shown the enhancement of antibody-dependent cellular cytotoxicity against neuroblastoma by activated iNKT cells. As a first step towards clinical application, we studied the frequency and proliferative response of circulating iNKT cells in children with and without cancer. METHODS: Blood samples were collected from 10 patients with pediatric malignant solid tumors and 11 patients with non-neoplastic diseases (control). The frequency of circulating iNKT cells was quantified by flow cytometry. Whole peripheral blood mononuclear cells were then stimulated with α-galactosylceramide (α-GalCer) for 7 days, and the expansion rate of the iNKT-cell fraction was assessed. RESULTS: The frequency of iNKT cells in the patients of the cancer and control group did not differ to a statistically significant extent. The iNKT-cell population increased after α-GalCer stimulation in all cases. The iNKT cells of patients who had undergone intensive chemotherapy also had the potential to expand in vitro. CONCLUSIONS: Unlike adult cancer patients, the numbers of circulating iNKT cells were not decreased in pediatric cancer patients. α-GalCer stimulation induced a proliferative response in all of the patients.
Asunto(s)
Células T Asesinas Naturales/patología , Neuroblastoma/sangre , Adulto , Animales , Proliferación Celular , Niño , Preescolar , Citometría de Flujo , Humanos , Lactante , Recuento de Linfocitos , Masculino , Neuroblastoma/patología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Tumor immunity has been suggested to play a key role in clinical and biological behavior of neuroblastomas. Given that CD1-restricted invariant natural killer T (iNKT) cells enhance both innate and acquired tumor immunity, we investigated the expression of the iNKT-cell-specific T-cell receptor Vα24-Jα18 in neuroblastoma tissues and its correlation with clinical and biological characteristics. METHODS: Using real- time quantitative PCR, we quantified the expression of Vα24-Jα18 in untreated tumor samples from 107 neuroblastoma cases followed in our institution and analyzed the correlation between the presence of infiltrated iNKT cells and clinical characteristics or patients' outcome. RESULTS: Vα24-Jα18 receptor was detected in 62 untreated cases (57.9%). The expression was significantly higher in stages 1, 2, 3, or 4S (P = 0.0099), in tumors with low or intermediate risk (P = 0.0050), with high TrkA expression (P = 0.0229), with favorable histology (P = 0.0026), with aneuploidy (P = 0.0348), and in younger patients (P = 0.0036). The overall survival rate was significantly higher in patients with iNKT-cell infiltration (log-rank; P = 0.0089). CONCLUSIONS: Since tumor-infiltrating iNKT cells were predominantly observed in neuroblastomas undergoing spontaneous differentiation and/or regression, we suggest that iNKT cells might play a key role in these processes.
Asunto(s)
ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Proteína Proto-Oncogénica N-Myc/genética , Células T Asesinas Naturales/patología , Neuroblastoma/genética , Receptores de Antígenos de Linfocitos T/genética , Southern Blotting , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Mucosa Intestinal , Masculino , Proteína Proto-Oncogénica N-Myc/biosíntesis , Células T Asesinas Naturales/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Antígenos de Linfocitos T/biosíntesisRESUMEN
The immunoregulatory functions of vitamin D have been well documented in various immunological disorders, including multiple sclerosis, arthritis, and asthma. IL-10 is considered a chief effector molecule that promotes the vitamin D-induced immunosuppressive states of T cells and accessory cells. In this article, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), has a profound inhibitory effect on the development of human Th9, a CD4 T cell subset that is highly associated with asthma, in an IL-10-independent manner. Our data show that calcitriol represses the expression of BATF, a transcription factor essential for Th9, via suppressing the expression of aryl hydrocarbon receptor, without an increase in IL-10. The data show a novel link between vitamin D and two key transcription factors involved in T cell differentiation.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Calcitriol/farmacología , Diferenciación Celular/inmunología , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Linfocitos T Colaboradores-Inductores/citología , Asma/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/biosíntesis , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Diferenciación Celular/efectos de los fármacos , Humanos , Interleucina-10/antagonistas & inhibidores , Interleucina-10/inmunología , Activación de Linfocitos/inmunología , Interferencia de ARN , ARN Interferente Pequeño , Receptores de Hidrocarburo de Aril/biosíntesis , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Anti-ganglioside GD2 antibodies mainly work through antibody-dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high-risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti-GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti-tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti-GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcγR, iNKT cells were not directly associated with ADCC. When co-cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNγ) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti-GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK-NKT cell contact or NK cell-dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNγ production by iNKT cells and NK cells. In conclusion, iNKT cell-based immunotherapy could be an appropriate candidate for anti-GD2 antibody therapy for neuroblastoma.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Células T Asesinas Naturales/inmunología , Neuroblastoma/terapia , Animales , Antígenos CD1d/metabolismo , Línea Celular Tumoral , Citocinas , Humanos , Activación de Linfocitos , Ratones , Neuroblastoma/inmunologíaRESUMEN
The role of invariant natural killer T (iNKT) cells in antitumor immunity has been studied extensively, and clinical trials in patients with advanced cancer have revealed a prolonged survival in some cases. In recent years, humanized blocking antibodies against co-stimulatory molecules such as PD-1 have been developed. The enhancement of T cell function is reported to improve antitumor immunity, leading to positive clinical effects. However, there are limited data on the role of PD-1/programmed death ligand (PDL) molecules in human iNKT cells. In this study, we investigated the interaction between PD-1 on iNKT cells and PDL on antigen-presenting cells (APCs) in the context of iNKT cell stimulation. The blockade of PDL1 at the time of stimulation resulted in increased release of helper T cell (Th) 1 cytokines from iNKT cells, leading to the activation of NK cells. The direct antitumor function of iNKT cells was also enhanced after stimulation with anti-PDL1 antibody-treated APCs. According to these results, we conclude that the co-administration of anti-PDL1 antibody and alpha-galactosylceramide (αGalCer)-pulsed APCs enhances iNKT cell-mediated antitumor immunity.
Asunto(s)
Células T Asesinas Naturales/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Animales , Femenino , Humanos , Ligandos , Ratones , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Naturally arising CD4(+)CD25(+)FoxP3(+) regulatory T cells (nTregs) have an essential role in maintenance of immune homeostasis and peripheral tolerance. Previously, we reported that conventional CD4(+) and CD8(+) T cells undergo p53-induced CD28-dependent apoptosis (PICA) when stimulated with a combination of immobilized anti-CD3 and anti-CD28 Abs, whereas nTregs expand robustly under the same conditions, suggesting that there is a differential survival mechanism against PICA between conventional T cells and nTregs. In this study, we demonstrate that TGF-ß signaling is required for nTregs to survive PICA. Conversely, when an active form of exogenous TGF-ß is present, conventional T cells become resistant to PICA and undergo robust expansion instead of apoptosis, with reduction of the proapoptotic protein Bim and FoxO3a. A substantial fraction of PICA-resistant T cells expressed IL-9 (T(H)9 cells). Moreover, the presence of IL-6 along with TGF-ß led to the generation of T(H)17 cells from conventional T cells. Together, the data demonstrate a novel role for TGF-ß in the homeostasis of regulatory T cells and effector T cell differentiation and expansion.
Asunto(s)
Apoptosis/inmunología , Diferenciación Celular/inmunología , Transducción de Señal/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Proteína 11 Similar a Bcl2 , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/genética , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-9/genética , Interleucina-9/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/inmunología , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Invariant natural killer T (iNKT) cells are a small subset of T lymphocytes that release large amounts of cytokines such as IFN-γ and exhibit cytotoxic activity upon activation, inducing strong anti-tumor effects. Harnessing the anti-tumor properties of iNKT cells, iNKT cell-based immunotherapy has been developed to treat cancer patients. In one of the iNKT cell-based immunotherapies, two approaches are utilized, namely, active immunotherapy or adoptive immunotherapy, the latter involving the ex vivo expansion and subsequent administration of iNKT cells. There are two sources of iNKT cells for adoptive transfer, autologous and allogeneic, each with its own advantages and disadvantages. Here, we assess clinical trials conducted over the last decade that have utilized iNKT cell adoptive transfer as iNKT cell-based immunotherapy, categorizing them into two groups based on the use of autologous iNKT cells or allogeneic iNKT cells.
Asunto(s)
Inmunoterapia Adoptiva , Células T Asesinas Naturales , Neoplasias , Células T Asesinas Naturales/inmunología , Humanos , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Neoplasias/inmunología , Animales , Ensayos Clínicos como Asunto , Células Alogénicas/inmunología , Trasplante AutólogoRESUMEN
Invariant natural killer T (iNKT) cells play an essential role in antitumor immunity by exerting cytotoxicity and producing massive amounts of cytokines. iNKT cells express invariant T-cell receptors (TCR) to recognize their cognate glycolipid antigens such as α-galactosylceramide (α-GalCer) presented on CD1d. We recently reported that iNKT cells recognize CD1d-negative leukemia cell line K562 in a TCR-dependent manner. However, it remains controversial how iNKT cells use TCRs to recognize and exhibit cytotoxic activity toward CD1d-negative tumors cells without CD1d restriction. Here, we report that iNKT cells exerted cytotoxicity toward K562 cells via a carried over anti-Vα24 TCR mAb from positive selection by magnetic bead sorting. We found that addition of the anti-Vα24Jα18 TCR mAb (6B11 mAb) rendered iNKT cells cytotoxic to K562 cells in an FcγRII (CD32)-dependent manner. Moreover, iNKT cells treated with 6B11 mAb became cytotoxic to other CD32+ cell lines (U937 and Daudi). In addition, iNKT cells treated with 6B11 mAb suppressed K562 cell growth in a murine xenograft model in vivo. These data suggest that anti-iNKT TCR mAb treatment of iNKT cells can be applied as a therapeutic strategy to treat CD32+ cancers such as leukemia, lymphoma, and lung cancer. SIGNIFICANCE: Our findings unveiled that iNKT cells recognize and kill CD1d-negative target tumors via the anti-iNKT TCR mAb bound to CD32 at the tumor site, thereby bridging iNKT cells and CD1d-negative tumors. These findings shed light on the therapeutic potential of anti-iNKT TCR mAbs in NKT cell-based immunotherapy to treat CD1d-negative CD32+ cancers.
Asunto(s)
Leucemia , Células T Asesinas Naturales , Humanos , Ratones , Animales , Receptores de Antígenos de Linfocitos T/metabolismo , Línea Celular , Citocinas/metabolismo , Leucemia/metabolismoRESUMEN
Ag receptor stimulation of preactivated T cells causes rapid cell death in an IL-2- and Fas-dependent manner. This phenomenon, known as activation-induced cell death (AICD), plays a pivotal role in the removal of Ag-reactive T cells after initial expansion. In this study, we report a novel form of T cell apoptosis that is distinct from classic AICD. When peripheral T cells were activated with anti-CD3 and anti-CD28 Abs precoated onto plastic plates, CD4(+)CD25(-) and CD8 T cells initially expanded but underwent massive apoptosis after 4 d. Unlike classic AICD, this type of T cell apoptosis pathway requires engagement of CD28 and expression of p53, a tumor-suppressor gene. The most striking feature of this form of apoptosis was regulatory T cell resistance. Under the same stimulating conditions, CD4(+)CD25(+) T cells grew continuously beyond 4 d. Consequently, when the entire CD4 population was cultured with plate-bound anti-CD3 plus anti-CD28 Ab, CD4(+)CD25(+)FoxP3(+) regulatory T cells outgrew nonregulatory T cells and expanded >7000-fold after 11 d. The data presented herein demonstrate a novel process of Ag-induced T cell death by sustained TCR and CD28 engagement and represent a simple and efficient procedure for the expansion of regulatory T cells in vitro.
Asunto(s)
Apoptosis/inmunología , Antígenos CD28/inmunología , Subgrupos de Linfocitos T/citología , Linfocitos T Reguladores/citología , Proteína p53 Supresora de Tumor/inmunología , Receptor fas/inmunología , Animales , Western Blotting , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Citometría de Flujo , Ratones , Ratones Noqueados , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Receptor fas/metabolismoRESUMEN
INTRODUCTION: Internal hernias are rare after laparoscopic colorectal resections. We report a patient with an internal hernia through a defect in the transverse mesocolon following laparoscopic resection. PRESENTATION OF CASE: A 52-year-old male underwent laparoscopic colectomy for transverse colon cancer and had an unremarkable postoperative course. Thirty days postoperatively, he presented to the emergency room with sudden onset abdominal pain and vomiting. Enhanced abdominal computed tomography scan showed strangulated small intestine in the left upper abdomen. An internal hernia through the mesenteric defect created during the recent colon resection was suspected, and emergency laparotomy was performed. One hundred thirty cm of small intestine was found herniated through a mesenteric defect. After repositioning the ischemic-appearing intestine, a 5â¯cm defect in the transverse mesocolon was found which had not been closed during the previous laparoscopic operation. No intestinal resection was needed, and the mesenteric defect closed with non-absorbable sutures. The post-operative course was unremarkable except for paralytic ileus, which resolved without further intervention. DISCUSSION: The incidence of internal hernia through a mesenteric defect after laparoscopic colorectal resection is quite low. Therefore, routine closure of the mesenteric defect after laparoscopic colorectal resection is not required. However, a left sided defect in the transverse mesocolon might be at higher risk of causing an internal hernia on anatomic grounds. CONCLUSION: We believe that mesenteric defects should be closed after laparoscopic resection of the left side of transverse colon, regardless of their size.
RESUMEN
BACKGROUND: Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC. METHODS: Patients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan. RESULTS: Thirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs. CONCLUSIONS: The intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy. TRIAL REGISTRATION NUMBER: UMIN000007321.
Asunto(s)
Células Presentadoras de Antígenos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Galactosilceramidas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to T-cell receptor (TCR) stimulation by recognizing antigens such as α-galactosylceramide (α-GalCer) presented on CD1d; thus, orchestrating other immune cells to fight against pathogen infection and tumors. Because of their ability to induce strong anti-tumor responses and the convenience of their invariant TCR activated by a synthetic ligand, α-GalCer, iNKT cells have been intensively studied for application in immunotherapeutic approaches to treat cancer patients in the clinic. Here, we summarize the clinical trials of iNKT cell based immunotherapy for non-small cell lung cancer, and head and neck cancer. Although solid tumors are thought to be refractory to immunotherapeutic approaches, our clinical trials showed that the intravenous injection of α-GalCer-pulsed antigen presenting cells (APCs) activated endogenous iNKT cells and iNKT cell dependent responses. Moreover, an increase in the number of IFN-γ producing cells in PBMCs was associated with prolonged survival. The marked infiltration of iNKT cells and the accumulation of conventional T cells in the tumor microenvironment were also observed after the administration of α-GalCer-pulsed APCs and/or ex vivo activated iNKT cells. In cases of advanced head and neck squamous cell carcinoma, the increased accumulation of iNKT cells in the tumor microenvironment was correlated with objective clinical responses. We will also discuss potential combination therapies of iNKT cell based immunotherapy to achieve enhanced anti-tumor activity and provide better treatment options for these patients.
Asunto(s)
Susceptibilidad a Enfermedades/inmunología , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/metabolismo , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Ensayos Clínicos como Asunto , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/terapia , Humanos , Inmunoterapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Resultado del Tratamiento , Microambiente Tumoral/inmunologíaRESUMEN
The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphoid organs called milky spots. The omentum has been used for its healing potential for over 100 years by transposing the omental pedicle to injured organs (omental transposition), but the mechanism by which omentum helps the healing process of damaged tissues is not well understood. Omental transposition promotes expansion of pancreatic islets, hepatocytes, embryonic kidney, and neurons. Omental cells (OCs) can be activated by foreign bodies in vivo. Once activated, they become a rich source for growth factors and express pluripotent stem cell markers. Moreover, OCs become engrafted in injured tissues suggesting that they might function as stem cells.Omentum consists of a variety of phenotypically and functionally distinctive cells. To understand the mechanism of tissue repair support by the omentum in more detail, we analyzed the cell subsets derived from the omentum on immune and inflammatory responses. Our data demonstrate that the omentum contains at least two groups of cells that support tissue repair, immunomodulatory myeloid derived suppressor cells and omnipotent stem cells that are indistinguishable from mesenchymal stem cells. Based on these data, we propose that the omentum is a designated organ for tissue repair and healing in response to foreign invasion and tissue damage.