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1.
Cell ; 186(7): 1432-1447.e17, 2023 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-37001503

RESUMEN

Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.


Asunto(s)
Melanoma , Linfocitos T , Ratones , Animales , Linfocitos T/patología , Neutrófilos/patología , Deriva y Cambio Antigénico , Inmunoterapia , Antígeno CTLA-4
2.
J Immunol ; 203(7): 2011-2019, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31434709

RESUMEN

OX40 is a costimulatory molecule from the TNFR family. In mice, it is expressed on Foxp3+ regulatory T cells (Tregs) constitutively and on conventional CD4 (Tconv) and CD8 T cells after Ag encounter. OX40 agonists are in clinical development to enhance antitumor immune responses, and one proposed mechanism of action is loss of Treg suppressive function. Studies have postulated that agonist OX40 therapy can impair Treg suppressive function. Using tools developed since the initial studies were published, we evaluated a direct effect of OX40 agonism on Treg function. We conclude that OX40 agonist Abs do not intrinsically impair Treg function but rather enhance Tconv cell IL-2 production, increasing Treg and Tconv cell proliferation. OX40-stimulated Tregs retain suppressive function, but also gain IFN-γ, TNF-α, and granzyme B expression. These data help resolve mechanistic questions regarding OX40 agonist immunotherapy and thus are relevant to developing combination therapies that target distinct T cell functions.


Asunto(s)
Anticuerpos Antineoplásicos/farmacología , Linfocitos T CD8-positivos/inmunología , Inmunoterapia , Proteínas de Neoplasias , Neoplasias , Receptores OX40 , Linfocitos T Reguladores/inmunología , Animales , Anticuerpos Antineoplásicos/inmunología , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Citocinas/genética , Citocinas/inmunología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/inmunología , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Receptores OX40/antagonistas & inhibidores , Receptores OX40/genética , Receptores OX40/inmunología , Linfocitos T Reguladores/patología
3.
J Immunol ; 197(6): 2509-21, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27503208

RESUMEN

Cancer cells harbor high-affinity tumor-associated Ags capable of eliciting potent antitumor T cell responses, yet detecting these polyclonal T cells is challenging. Therefore, surrogate markers of T cell activation such as CD69, CD44, and programmed death-1 (PD-1) have been used. We report in this study that in mice, expression of activation markers including PD-1 is insufficient in the tumor microenvironment to identify tumor Ag-specific T cells. Using the Nur77GFP T cell affinity reporter mouse, we highlight that PD-1 expression can be induced independent of TCR ligation within the tumor. Given this, we characterized the utility of the Nur77GFP model system in elucidating mechanisms of action of immunotherapies independent of PD-1 expression. Coexpression of Nur77GFP and OX40 identifies a polyclonal population of high-affinity tumor-associated Ag-specific CD8(+) T cells, which produce more IFN-γ in situ than OX40 negative and doubles in quantity with anti-OX40 and anti-CTLA4 mAb therapy but not with anti-PD-1 or programmed death ligand-1. Moreover, expansion of these high-affinity CD8 T cells prolongs survival of tumor-bearing animals. Upon chronic stimulation in tumors and after adoptive cell therapy, CD8 TCR signaling and Nur77GFP induction is impaired, and tumors progress. However, this can be reversed and overall survival significantly enhanced after adoptive cell therapy with agonist OX40 immunotherapy. Therefore, we propose that OX40 agonist immunotherapy can maintain functional TCR signaling of chronically stimulated tumor-resident CD8 T cells, thereby increasing the frequency of cytotoxic, high-affinity, tumor-associated Ag-specific cells.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunoterapia Adoptiva/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Receptor de Muerte Celular Programada 1/genética , Linfocitos T Citotóxicos/inmunología , Animales , Linfocitos T CD8-positivos/fisiología , Antígeno CTLA-4/inmunología , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/fisiología , Ratones , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores OX40/agonistas , Receptores OX40/genética , Subgrupos de Linfocitos T/inmunología , Microambiente Tumoral
4.
Immunol Rev ; 244(1): 218-31, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22017441

RESUMEN

OX40 (CD134) is a tumor necrosis factor (TNF) receptor expressed primarily on activated CD4(+) and CD8(+) T cells and transmits a potent costimulatory signal when engaged. OX40 is transiently expressed after T-cell receptor engagement and is upregulated on the most recently antigen-activated T cells within inflammatory lesions (e.g. sites of autoimmune destruction and on tumor-infiltrating lymphocytes). Hence, it is an attractive target to modulate immune responses: OX40 blocking agents to inhibit undesirable inflammation or OX40 agonists to enhance immune responses. In regards to this review, OX40 agonists enhance anti-tumor immunity, which leads to therapeutic effects in mouse tumor models. A team of laboratory and clinical scientists at the Providence Cancer Center has collaborated to bring the preclinical observations in cancer models from the bench to the bedside. This review describes the journey from in vitro experiments through preclinical mouse models to the successful translation of the first OX40 agonist to the clinic for the treatment of patients with cancer.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunidad Innata , Factores Inmunológicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Receptores OX40/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Expresión Génica/inmunología , Haplorrinos , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Factores Inmunológicos/administración & dosificación , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Activación de Linfocitos/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Noqueados , Neoplasias/inmunología , Neoplasias/patología , Ratas , Receptores OX40/agonistas , Receptores OX40/antagonistas & inhibidores , Receptores OX40/genética , Investigación Biomédica Traslacional
5.
Cancer Immunol Immunother ; 63(6): 615-26, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24682539

RESUMEN

Immune responses wane during aging, posing challenges to the potential effectiveness of cancer immunotherapies. We previously demonstrated that in the context of a promising immunotherapeutic, OX40 agonist (αOX40), older animals exhibited impaired anti-tumor immune responses and diminished CD4 T cell effector differentiation. In this study, we hypothesized that tumor immune responses could be maintained during aging through caloric restriction (CR) or dietary supplementation with resveratrol (RES), a CR mimetic. Mice were placed on either a calorically restricted diet or a RES-formulated diet starting between 4 and 6 months of age and continued until mice reached 12 months of age. Tumor immune responses were assessed after challenging with either sarcoma or breast tumor cells followed by αOX40 treatment. Our results show that CR, but not RES, maintained OX40-mediated anti-tumor immunity. In addition, CR fully sustained antigen-specific CD4 T cell priming in aged hosts (12 months old), whereas tumor-specific CD8 T cell priming was not fully maintained compared to young reference animals (2 months old). Thus, CR appears to maintain immunological fitness of the CD4 T cell priming environment during aging, which is critical for optimal OX40-mediated responses.


Asunto(s)
Envejecimiento/inmunología , Anticarcinógenos/farmacología , Linfocitos T CD4-Positivos/inmunología , Restricción Calórica , Neoplasias Experimentales/inmunología , Receptores OX40/agonistas , Estilbenos/farmacología , Traslado Adoptivo , Animales , Western Blotting , Femenino , Citometría de Flujo , Humanos , Inmunoterapia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias Experimentales/mortalidad , Neoplasias Experimentales/terapia , Resveratrol , Tasa de Supervivencia , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología
6.
Eur J Immunol ; 42(7): 1893-905, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22585674

RESUMEN

Surface expression of the IL-2 receptor α-chain (CD25) has been used to discriminate between CD4(+) CD25(HI) FOXP3(+) regulatory T (Treg) cells and CD4(+) CD25(NEG) FOXP3(-) non-Treg cells. However, this study reports that the majority of resting human memory CD4(+) FOXP3(-) T cells expresses intermediate levels of CD25 and that CD25 expression can be used to delineate a functionally distinct memory subpopulation. The CD25(NEG) memory T-cell population contains the vast majority of late differentiated cells that respond to antigens associated with chronic immune responses and are increased in patients with systemic lupus erythematosus (SLE). In contrast, the CD25(INT) memory T cells respond to antigens associated with recall responses, produce a greater array of cytokines, and are less dependent on costimulation for effector responses due to their expression of CD25. Lastly, compared to the CD25(NEG) and Treg-cell populations, the CD25(INT) memory population is lost to a greater degree from the blood of cancer patients treated with IL-2. Collectively, these results show that in humans, a large proportion of CD4(+) memory T cells express intermediate levels of CD25, and this CD25(INT) FOXP3(-) subset is a functionally distinct memory population that is uniquely affected by IL-2.


Asunto(s)
Factores de Transcripción Forkhead/inmunología , Memoria Inmunológica/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Neoplasias Renales/inmunología , Lupus Eritematoso Sistémico/inmunología , Melanoma/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación/métodos , Interleucina-2/uso terapéutico , Neoplasias Renales/sangre , Neoplasias Renales/tratamiento farmacológico , Lupus Eritematoso Sistémico/sangre , Masculino , Melanoma/sangre , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Adulto Joven
7.
Immunology ; 136(4): 437-47, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22578109

RESUMEN

The treatment of high-grade tumours must consider a tumour environment dominated by cells that support cancer growth. In addition to directing angiogenesis and invasion, alternatively activated macrophages in the tumour provide protection from adaptive immunity and permit tumour growth. Agonist antibodies to the tumour necrosis factor receptor family member OX40 are an effective therapy for cancer in a range of murine models; however, as with many immune therapies, αOX40 therapy is less effective as the tumour grows and develops an immune suppressive environment. We demonstrate that αOX40 directly activates T cells and that this T-cell activation alters macrophage differentiation in the tumour environment. We demonstrate that macrophages in the tumour limit the efficacy of αOX40 therapy, and that combining αOX40 therapy with inhibitors of arginase significantly enhances survival of tumour-bearing mice. These data demonstrate that macrophages in the tumour environment limit the effectiveness of OX40-based immunotherapy, and combination therapies that target both the cell-mediated immune response and the suppressive tumour environment will be required for translation of effective immunotherapies to patients with established tumours.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunoterapia , Macrófagos/inmunología , Neoplasias Experimentales/terapia , Receptores OX40/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Arginasa/antagonistas & inhibidores , Diferenciación Celular , Interferón gamma/metabolismo , Interleucina-12/farmacología , Interleucina-18/farmacología , Activación de Linfocitos , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/inmunología , Receptores OX40/agonistas , Microambiente Tumoral/inmunología
8.
Eur J Immunol ; 41(4): 1024-34, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21400495

RESUMEN

OX40 engagement on activated T cells leads to increased proliferation, expansion and survival of Ag-specific T cells. Direct ex vivo examination of Ag-stimulated murine T cells show that the Myc antagonists, Mxd4 and Mnt, are transiently upregulated and translocated to the nucleus following OX40 engagement and may be involved in suppressing cell death. Both Mxd4 and Mnt are upregulated following OX40 stimulation through increased protein stability and we identify a critical phosphorylation site in Mxd4 that controls Mxd4 stability. The upregulation of Mxd4 and Mnt contributes to OX40-mediated T-cell survival because siRNA knockdown of Mxd4 and Mnt led to increased cell death. We hypothesize the upregulation of c-Myc following OX40 engagement drives T-cell proliferation and that upregulation of Mxd4 and Mnt suppresses Myc-dependent cell death. Thus, Mxd4 and Mnt upregulation following OX40 engagement most likely increases T-cell survival.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/inmunología , Activación de Linfocitos , Receptores OX40/inmunología , Proteínas Represoras/inmunología , Linfocitos T/inmunología , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Línea Celular , Supervivencia Celular , Femenino , Humanos , Ratones , Fosfoserina/metabolismo , Proteínas Proto-Oncogénicas c-myb/inmunología , ARN Interferente Pequeño , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Linfocitos T/citología
9.
Cancer Immunol Immunother ; 61(4): 511-21, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21971588

RESUMEN

Effective tumor immunotherapy may require not only activation of anti-tumor effector cells, but also abrogation of tumor-mediated immunosuppression. The cytokine TGF-ß, is frequently elevated in the tumor microenvironment and is a potent immunosuppressive agent and promoter of tumor metastasis. OX40 (CD134) is a member of the TNF-α receptor superfamily and ligation by agonistic antibody (anti-OX40) enhances effector function, expansion, and survival of activated T cells. In this study, we examined the therapeutic efficacy and anti-tumor immune response induced by the combination of a small molecule TGF-ß signaling inhibitor, SM16, plus anti-OX40 in the poorly immunogenic, highly metastatic, TGF-ß-secreting 4T1 mammary tumor model. Our data show that SM16 and anti-OX40 mutually enhanced each other to elicit a potent anti-tumor effect against established primary tumors, with a 79% reduction in tumor size, a 95% reduction in the number of metastatic lung nodules, and a cure rate of 38%. This positive treatment outcome was associated with a 3.2-fold increase of tumor-infiltrating, activated CD8+ T cells, an overall accumulation of CD4+ and CD8+ T cells, and an increased tumor-specific effector T cell response. Complete abrogation of the therapeutic effect in vivo following depletion of CD4+ and CD8+ T cells suggests that the anti-tumor efficacy of SM16+ anti-OX40 therapy is T cell dependent. Mice that were cured of their tumors were able to reject tumor re-challenge and manifested a significant tumor-specific peripheral memory IFN-γ response. Taken together, these data suggest that combining a TGF-ß signaling inhibitor with anti-OX40 is a viable approach for treating metastatic breast cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos de Azabiciclo/administración & dosificación , Carcinoma/tratamiento farmacológico , Inmunoterapia , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Compuestos de Azabiciclo/efectos adversos , Carcinoma/patología , Progresión de la Enfermedad , Sinergismo Farmacológico , Femenino , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Trasplante de Neoplasias , Receptores OX40/agonistas , Receptores OX40/inmunología , Transducción de Señal/efectos de los fármacos , Carga Tumoral
10.
J Immunol ; 185(8): 4856-62, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20844189

RESUMEN

The initial phase of sepsis is characterized by massive inflammatory cytokine production that contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity. Recent studies described their presence on neutrophils and monocytes, suggesting a potential role in the regulation of cytokine production in innate immunity. The purpose of this study was to determine the role for OX40-OX40 ligand (OX40L) interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on monocytes and neutrophils, with mortality and intensive care unit stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was indicated by improved survival, decreased cytokine production, and a decrease in remote organ damage in OX40L(-/-) mice. The finding of similar results with an OX40L Ab suggests a potential therapeutic role for OX40L blockade in sepsis. The inability of anti-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensable cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of anti-OX40L Ab in RAG1(-/-) mice further confirms a T cell-independent role for OX40L stimulation in sepsis. In conclusion, our data provide an in vivo role for the OX40/OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.


Asunto(s)
Inmunidad Innata , Glicoproteínas de Membrana/inmunología , Ligando OX40/inmunología , Sepsis/inmunología , Factores de Necrosis Tumoral/inmunología , Adulto , Animales , Separación Celular , Femenino , Citometría de Flujo , Humanos , Inmunoensayo , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Ligando OX40/metabolismo , Receptores OX40/inmunología , Receptores OX40/metabolismo , Sepsis/metabolismo , Sepsis/mortalidad , Factores de Necrosis Tumoral/metabolismo
11.
Front Immunol ; 13: 896310, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36238275

RESUMEN

To prevent SARS-CoV-2 infections and generate long-lasting immunity, vaccines need to generate strong viral-specific B and T cell responses. Previous results from our lab and others have shown that immunizations in the presence of an OX40 agonist antibody lead to higher antibody titers and increased numbers of long-lived antigen-specific CD4 and CD8 T cells. Using a similar strategy, we explored the effect of OX40 co-stimulation in a prime and boost vaccination scheme using an adjuvanted SARS-CoV-2 spike protein vaccine in C57BL/6 mice. Our results show that OX40 engagement during vaccination significantly increases long-lived antibody responses to the spike protein. In addition, after immunization spike protein-specific proliferation was greatly increased for both CD4 and CD8 T cells, with enhanced, spike-specific secretion of IFN-γ and IL-2. Booster (3rd injection) immunizations combined with an OX40 agonist (7 months post-prime) further increased vaccine-specific antibody and T cell responses. Initial experiments assessing a self-amplifying mRNA (saRNA) vaccine encoding the spike protein antigen show a robust antigen-specific CD8 T cell response. The saRNA spike-specific CD8 T cells express high levels of GrzmB, IFN-γ and TNF-α which was not observed with protein immunization and this response was further increased by the OX40 agonist. Similar to protein immunizations the OX40 agonist also increased vaccine-specific CD4 T cell responses. In summary, this study compares and contrasts the effects and benefits of both protein and saRNA vaccination and the extent to which an OX40 agonist enhances and sustains the immune response against the SARS-CoV-2 spike protein.


Asunto(s)
COVID-19 , Vacunas , Animales , COVID-19/prevención & control , Humanos , Interleucina-2 , Ratones , Ratones Endogámicos C57BL , ARN Mensajero , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Factor de Necrosis Tumoral alfa
12.
J Clin Invest ; 132(12)2022 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-35439168

RESUMEN

CD4+ Th cells play a key role in orchestrating immune responses, but the identity of the CD4+ Th cells involved in the antitumor immune response remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and colorectal cancers and identified a subset of CD4+ Th cells distinct from FOXP3+ Tregs that coexpressed programmed cell death 1 (PD-1) and ICOS. These tumor-infiltrating lymphocyte CD4+ Th cells (CD4+ Th TILs) had a tissue-resident memory phenotype, were present in MHC class II-rich areas, and proliferated in the tumor, suggesting local antigen recognition. The T cell receptor repertoire of the PD-1+ICOS+ CD4+ Th TILs was oligoclonal, with T cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4+ Th TILs were shown to recognize both tumor-associated antigens and tumor-specific neoantigens. Our findings provide an approach for isolating tumor-reactive CD4+ Th TILs directly ex vivo that will help define their role in the antitumor immune response and potentially improve future adoptive T cell therapy approaches.


Asunto(s)
Neoplasias de Cabeza y Cuello , Receptor de Muerte Celular Programada 1 , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Neoplasias de Cabeza y Cuello/patología , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles , Linfocitos Infiltrantes de Tumor , Receptor de Muerte Celular Programada 1/genética
13.
J Immunol ; 182(3): 1481-9, 2009 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-19155495

RESUMEN

OX40 agonists have potent immunotherapeutic effects against a variety of murine tumors, yet it is unclear the role that age-related immune senescence plays on their efficacy. We found that middle-aged and elderly tumor-bearing mice (12 and 20 mo old, respectively) treated with anti-OX40 were less responsive compared with young mice 6 mo or less of age. Decreased tumor-free survival was observed in both male and female mice, and was not due to changes in the surface expression of OX40 on T cells in older animals. Enumeration of cytokine-producing effector T cells in tumor-bearing mice revealed a significant decline in these cells in the older mice treated with anti-OX40 compared with their younger counterparts. The decrease of this critical T cell population in middle-aged mice was not a result of inherent T cell deficiencies, but was revealed to be T cell extrinsic. Finally, combining IL-12, an innate cytokine, with anti-OX40 boosted levels of differentiated effector T cells in the older anti-OX40-treated mice and partially restored the defective antitumor responses in the middle-aged mice. Our data show that the anti-OX40-enhancement of tumor immunity and effector T cell numbers is decreased in middle-aged mice and was partially reversed by coadministration of the proinflammatory cytokine IL-12.


Asunto(s)
Envejecimiento/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Diferenciación Celular/inmunología , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Receptores OX40/fisiología , Animales , Anticuerpos/administración & dosificación , Anticuerpos/uso terapéutico , Linfocitos T CD4-Positivos/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Neoplasias del Colon/fisiopatología , Neoplasias del Colon/prevención & control , Femenino , Rechazo de Injerto/metabolismo , Mediadores de Inflamación/administración & dosificación , Interleucina-12/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores OX40/antagonistas & inhibidores , Receptores OX40/inmunología , Sarcoma Experimental/inmunología , Sarcoma Experimental/fisiopatología , Sarcoma Experimental/prevención & control
14.
J Immunol ; 183(8): 4853-7, 2009 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-19786544

RESUMEN

We report that OX40 stimulation drives all lineages of CD4 T cell development, including regulatory T cells (Tregs), and the plasticity of the response is dependant on local cytokines. In TGF-beta1-treated cultures, an OX40 agonist increased IFN-gamma and IL-4 production and diverted T cells from the Treg lineage. However, cytokine blockade in the context of OX40 stimulation promoted enhanced Treg accumulation. This observation was evident in naive mice, as OX40 engagement enhanced Treg proliferation and accumulation in vivo. Lastly, OX40 agonist administration influenced experimental autoimmune encephalomyelitis disease severity in opposing directions, depending on the timing of administration. Given during Ag priming, the OX40 agonist drove Treg expansion and inhibited disease, whereas given later it enhanced T cell effector cytokine production in the CNS and exacerbated disease. Hence, OX40 signaling can augment the accumulation of all CD4 T cell lineages; however, its accentuation of immune responses may have vastly different biologic outcomes depending upon the local cytokine milieu.


Asunto(s)
Citocinas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Receptores OX40/agonistas , Linfocitos T Reguladores/efectos de los fármacos , Traslado Adoptivo , Animales , Anticuerpos/administración & dosificación , Anticuerpos/inmunología , Antígenos CD28/efectos de los fármacos , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Complejo CD3/efectos de los fármacos , Complejo CD3/inmunología , Complejo CD3/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Interferón gamma/antagonistas & inhibidores , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interferón gamma/farmacología , Interleucina-4/antagonistas & inhibidores , Interleucina-4/inmunología , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores OX40/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta1/farmacología
15.
Nat Commun ; 12(1): 1047, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594075

RESUMEN

Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRß sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.


Asunto(s)
Epítopos/inmunología , Terapia Neoadyuvante , Receptores OX40/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Biopsia , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Células Clonales , Supervivencia sin Enfermedad , Papillomavirus Humano 16/fisiología , Humanos , Estimación de Kaplan-Meier , Activación de Linfocitos/inmunología , Subgrupos Linfocitarios/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Terapia Neoadyuvante/efectos adversos , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores OX40/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Células del Estroma/metabolismo
16.
Eur J Immunol ; 39(8): 2184-94, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19672905

RESUMEN

Tumor-specific CD8 T-cell peripheral tolerance occurs through clonal deletion, suppression, and the induction of anergy and can limit the generation of anti-tumor immunity. Several groups have demonstrated that prostate cancer can render tumor-specific CD8 T cells anergic, suggesting reversing tumor-induced anergy may greatly augment anti-tumor immunity. Recent work has demonstrated that signaling through the OX40 (CD134) co-stimulatory receptor, a member of the TNFR super-family, can augment CD4 and CD8 T-cell expansion, differentiation, and the generation of memory cells. However, whether OX40 ligation can reverse CD8 T-cell anergy, and more specifically, tumor-induced CD8 T-cell anergy, remains unclear. In the current study, we demonstrate that OX40 ligation can reverse CD8 T-cell anergy to a prostate-specific self-Ag in non-tumor-bearing hosts. Furthermore, OX40 engagement reversed tumor-specific CD8 T-cell anergy and restored the proliferative capacity of tumor-reactive CD8 T cells, which attenuated tumor growth and enhanced the survival of tumor-bearing hosts. These data demonstrate that OX40 ligation can rescue the function of anergic self- or tumor-reactive CD8 T cells in vivo and suggests that OX40-mediated therapy may provide a novel means of boosting anti-tumor immunity by restoring the responsiveness of previously anergic tumor-specific CD8 T cells.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Anergia Clonal/inmunología , Neoplasias de la Próstata/inmunología , Receptores OX40/inmunología , Animales , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/inmunología , Línea Celular Tumoral , Anergia Clonal/genética , Citotoxicidad Inmunológica/inmunología , Citometría de Flujo , Inmunoterapia Adoptiva , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Selectina L/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Receptores OX40/genética , Transducción de Señal/inmunología , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo
17.
Crit Rev Immunol ; 29(3): 187-201, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19538134

RESUMEN

The extent of T-cell activation, proliferation, and survival that follows T-cell receptor (TCR) ligation is controlled by several factors, including the strength of TCR stimulation, the availability of prosurvival cytokines, and the presence or absence of co-stimulatory signals. In addition to engagement of the CD28 co-stimulatory receptor by its natural ligands, B7.1 (CD80) and B7.2 (CD86), recent work has begun to elucidate the mechanisms by which signaling through the OX40 (CD134) co-stimulatory receptor, a member of the tumor necrosis factor receptor (TNFR) superfamily, affects T-cell responses. Importantly, OX40 ligation has been shown to augment CD4 and CD8 T-cell clonal expansion, effector differentiation, survival, and in some cases, abrogate the suppressive activity of regulatory FoxP3+CD25+CD4+ T cells. In this review, we focus on the mechanisms regulating OX40 expression on activated T cells as well as the role of OX40-mediated co-stimulation in boosting T-cell clonal expansion, effector differentiation, and survival.


Asunto(s)
Supervivencia Celular/inmunología , Activación de Linfocitos/inmunología , Receptores OX40/metabolismo , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Antígenos CD , Diferenciación Celular , Proliferación Celular , Factores de Transcripción Forkhead , Regulación de la Expresión Génica/inmunología , Humanos , Ligando OX40/genética , Ligando OX40/inmunología , Ligando OX40/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores OX40/genética , Receptores OX40/inmunología , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología
18.
Adv Exp Med Biol ; 684: 57-68, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20795540

RESUMEN

Memory T-cell generation is limited by activation-induced cell death during the effector T-cell stage. Cell surface proteins are known to transmit signals that either accentuate or limit T-cell death after activation. This chapter will focus on the TNF-receptor family member OX40, which is expressed on effector T cells and when engaged greatly enhances survival of T cells leading to increased memory T-cell generation. Targeting OX40 in vivo can alter the fate ofT-cell survival. Enhancing OX40 signaling during Ag priming through agonists increases memory T-cell development, while blocking OX40 signaling decreases the memory T-cell pool. These two opposing outcomes provide therapeutic tools for blocking inflammation in autoimmune conditions and enhancing immunity in hosts harboring cancer or chronic pathogens. OX40 agonists and antagonists are in the first stages of human clinical trials and their therapeutic potential will soon be realized.


Asunto(s)
Memoria Inmunológica/inmunología , Activación de Linfocitos , Receptores OX40/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Diferenciación Celular/inmunología , Humanos , Ratones , Neoplasias/inmunología , Neoplasias/terapia , Receptores OX40/agonistas , Transducción de Señal/inmunología
20.
Cancer Immunol Immunother ; 58(12): 1941-7, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19288101

RESUMEN

Agents that enhance T cell co-stimulatory signaling have emerged as promising cancer immunotherapies. Our laboratory has been evaluating the TNF receptor co-stimulatory molecule, OX40, which has the capacity to augment critical aspects of T cell function and induce tumor regression in animal models. Effective stimulation of OX40 expressing T cells was accomplished with agonist antibodies to OX40 that were eventually translated into a clinical trial for cancer patients. A recent attempt to assess the affect of immune senescence on OX40 therapy, revealed a dramatic loss of efficacy of the agonist therapy in older tumor-bearing mice. The deficiency in OX40-enhanced anti-tumor responses in older mice correlated with a decrease in the number of differentiated effector T cells. Further investigation suggests that the underlying age-related decline in the agonist OX40-mediated T cell responses was not inherent to the T cells themselves, but related to the host environment. Thus, effective use of immunotherapies based on T cell co-stimulatory molecules may require additional modifications, such as immune stimulants to increase innate immunity, to address age-related defects that reside outside of the T cell and within the host environment.


Asunto(s)
Envejecimiento/inmunología , Inmunoterapia/métodos , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/terapia , Receptores OX40/agonistas , Animales , Humanos , Ratones , Receptores OX40/inmunología , Receptores OX40/metabolismo , Linfocitos T/inmunología
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