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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.
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
3.
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
4.
J Investig Med High Impact Case Rep ; 9: 23247096211032821, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34269074

RESUMEN

Pulmonary hypertension (PH) is often a difficult condition to diagnose, since it occurs insidiously and is a diagnosis of exclusion. Patients with neurofibromatosis type 1 (NFT1) have been associated with severe exacerbations of PH. To our knowledge, less than 20 cases of PH in NFT1 patients have been reported. However, the severity of presenting symptoms requires physicians to be aware of this association and pursue the appropriate diagnostic workup. In our report, we present a 54-year-old NFT1 patient who presented with worsening dyspnea secondary to PH, which was being treated with trepostanil and macitetan. She required a right heart catheterization to assess her pulmonary artery pressures (which remained elevated). She was placed on tadalafil in addition to trepostanil and macitetan and noted significant resolution of her symptoms. Further studies are required to explore the association between PH and NFT1 and examine the efficacy of triple therapy with endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and parenteral prostanoids in the initial treatment of PH in the aforementioned patient population.


Asunto(s)
Hipertensión Pulmonar , Neurofibromatosis 1 , Femenino , Humanos , Hipertensión Pulmonar/etiología , Incidencia , Persona de Mediana Edad , Neurofibromatosis 1/complicaciones
5.
J Investig Med High Impact Case Rep ; 9: 23247096211005064, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33764182

RESUMEN

Commonly, pericardial effusions can cause suboptimal heart contractility. Larger pericardial effusions can lead to compression of structures that surround in the heart in the mediastinum. Our patient presented with dyspnea that required mechanical ventilation. Bronchoscopy revealed compression of the bronchus from an external source. Echocardiogram showed a large circumferential pericardial effusion, which compressed the left main stem bronchus causing left lung atelectasis and persistent respiratory failure. A subxiphoid pericardial window was performed, which led to an improvement in her oxygen requirements. This case portrays the importance of including pericardial effusions in patients who present with respiratory failure refractory to antibiotic treatment and intervention with bronchoscopy. Although our patient passed away, recognition and earlier appropriate management with a pericardial window or pericardiocentesis could have prevented this adverse event.


Asunto(s)
Derrame Pericárdico , Ecocardiografía , Femenino , Humanos , Derrame Pericárdico/etiología , Derrame Pericárdico/cirugía , Pericardiocentesis
6.
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
7.
Cureus ; 12(8): e9574, 2020 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-32782894

RESUMEN

Lyme disease is a multisystemic infection that can present as localized disease, early disseminated, or late disease. During the early disseminated phase of Lyme disease, the hematogenous spread can result in extracutaneous manifestations, including cardiac, neurological, and joint. Lyme carditis is an uncommon manifestation occurring in patients with untreated Lyme disease. Third-degree atrioventricular (AV) block is a rarer entity. We present a case of a 21-year-old female with no significant past medical history admitted with third-degree AV block and thereby highlighting this uncommon presentation.

8.
Front Oncol ; 9: 720, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31428586

RESUMEN

Malignant Mesothelioma (MM) is a rare and highly aggressive cancer that develops from mesothelial cells lining the pleura and other internal cavities, and is often associated with asbestos exposure. To date, no effective treatments have been made available for this pathology. Herein, we propose a novel immunotherapeutic approach based on a unique vaccine targeting a series of antigens that we found expressed in different MM tumors, but largely undetectable in normal tissues. This vaccine, that we term p-Tvax, is comprised of a series of immunogenic peptides presented by both MHC-I and -II to generate robust immune responses. The peptides were designed using in silico algorithms that discriminate between highly immunogenic T cell epitopes and other harmful epitopes, such as suppressive regulatory T cell epitopes and autoimmune epitopes. Vaccination of mice with p-Tvax led to antigen-specific immune responses that involved both CD8+ and CD4+ T cells, which exhibited cytolytic activity against MM cells in vitro. In mice carrying MM tumors, p-Tvax increased tumor infiltration of CD4+ T cells. Moreover, combining p-Tvax with an OX40 agonist led to decreased tumor growth and increased survival. Mice treated with this combination immunotherapy displayed higher numbers of tumor-infiltrating CD8+ and CD4+ T cells and reduced T regulatory cells in tumors. Collectively, these data suggest that the combination of p-Tvax with an OX40 agonist could be an effective strategy for MM treatment.

9.
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
10.
Cancer Immunol Res ; 7(2): 269-281, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30563828

RESUMEN

The protective capability of tumor antigen-specific T cells is regulated by costimulatory and inhibitory signals. Current approaches in cancer immunotherapy seek to restore the function of unresponsive T cells by blocking inhibitory pathways. In contrast, providing exogenous costimulatory signals to T cells also enhances antitumor functionality. By combining these two clinical approaches, we demonstrate the synergy of targeting PD-L1 together with the costimulatory molecule OX40, to enhance antitumor immunity. Concurrently blocking PD-L1 and providing a costimulatory agonist to OX40 increased the presence and functionality of tumor antigen-specific CD8+ T cells with simultaneous enhancement of T-helper type 1 (Th1)-skewed CD4+ T cells. This shift was functionally supported by increased glucose metabolism of antigen-specific CD8+ T cells and the acquisition of granzyme B by regulatory T cells. Together, this mechanism promoted tumor regression of late-stage tumors beyond that achieved by either blockade as monotherapy. These findings indicate that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias/inmunología , Neoplasias/metabolismo , Receptores OX40/agonistas , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Genome Med ; 11(1): 87, 2019 12 30.
Artículo en Inglés | MEDLINE | ID: mdl-31888734

RESUMEN

BACKGROUND: The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers. METHODS: Whole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material. RESULTS: Neoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39+CD103+ T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-ß pathway activation and worse clinical outcome. CONCLUSIONS: We have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-ß pathway to reinforce T cell reactivity in this patient group.


Asunto(s)
Antígenos de Neoplasias/inmunología , Neoplasias Colorrectales/patología , Antígenos de Neoplasias/química , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Reparación de la Incompatibilidad de ADN , Proteínas de Unión al ADN/genética , Epítopos/química , Epítopos/inmunología , Epítopos/farmacología , Humanos , Inmunoterapia , Interferón gamma/metabolismo , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Proteínas de Microfilamentos/genética , Mutación , Péptidos/síntesis química , Péptidos/farmacología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/metabolismo , Factores de Transcripción/genética , Factor de Crecimiento Transformador beta/metabolismo
12.
Nat Commun ; 9(1): 2724, 2018 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-30006565

RESUMEN

Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103+CD39+ tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103+CD39+ CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103+CD39+ CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies.


Asunto(s)
Antígenos CD/genética , Apirasa/genética , Antígenos CD8/genética , Linfocitos T CD8-positivos/inmunología , Cadenas alfa de Integrinas/genética , Linfocitos Infiltrantes de Tumor/inmunología , Transcriptoma , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Antígenos CD/inmunología , Apirasa/inmunología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Inmunofenotipificación , Cadenas alfa de Integrinas/inmunología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Melanoma/genética , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Análisis de Supervivencia
13.
Mol Cancer Ther ; 17(5): 1024-1038, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29545330

RESUMEN

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. Mol Cancer Ther; 17(5); 1024-38. ©2018 AACR.


Asunto(s)
Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunoglobulina G/inmunología , Ligando OX40/inmunología , Proteínas Recombinantes de Fusión/inmunología , Animales , Línea Celular Tumoral , Citocinas/inmunología , Citocinas/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Citotoxicidad Inmunológica/inmunología , Femenino , Células HEK293 , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoglobulina G/genética , Inmunoglobulina G/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Macaca mulatta , Ligando OX40/genética , Ligando OX40/metabolismo , Multimerización de Proteína/inmunología , Receptores OX40/agonistas , Receptores OX40/inmunología , Receptores OX40/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/farmacología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
15.
Sci Rep ; 6: 37558, 2016 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-27874054

RESUMEN

It is well-known that vaccines comprising of irradiated whole tumor cells or tumor-derived heat shock proteins can generate tumor-specific immune responses. In contrast, we showed recently that vaccines composed of autophagosomes (DRibbles) derived from syngeneic sarcomas could induce cross-reactive T-cell responses and cross-protection against the tumor. This unusual property of DRibbles was related to the selective recruitment of defective ribosomal products (DRiPs) and other short-lived proteins (SLiPs) into autophagosomes via sequestosome (SQSTM1, p62) mediated association of ubiquitinated SLiPs to the autophagy gene product LC3. Here, we extend our observations to mammary carcinomas from mice of different genetic background. We demonstrated that combined of intranodal administration of autologous or allogeneic DRibbles together with anti-OX40 antibody led to robust proliferation, expansion, and differentiation of memory and effector T cells. We also showed that SLiPs is an excellent source of antigen for cross-priming of CD8+ T-cells that recognize shared tumor antigens in the context of host MHC class I molecules. Thus, our results provide a strong basis for novel clinical trials that combine allogeneic "off-the-shelf" DRibble vaccines together with antibodies against co-stimulatory molecules.


Asunto(s)
Antígenos de Diferenciación/inmunología , Vacunas contra el Cáncer/inmunología , Inmunoterapia , Neoplasias Mamarias Animales/terapia , Animales , Antígenos de Neoplasias/inmunología , Autofagosomas/inmunología , Autofagia/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Reacciones Cruzadas/inmunología , Activación de Linfocitos/inmunología , Neoplasias Mamarias Animales/inmunología , Neoplasias Mamarias Animales/patología , Ratones , Proteína Sequestosoma-1/inmunología
16.
Oral Oncol ; 61: 166-76, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27614589

RESUMEN

Cytoreductive surgery is an approach to cancer treatment that aims to reduce the number of cancer cells via resection of primary tumor or metastatic deposits, in an effort to minimize a potentially immunosuppressive tumor burden, palliate symptoms, and prevent complications. Furthermore, it provides a platform for investigation of biomarkers with the goal of optimizing immunotherapy to reverse the immunosuppressive tumor microenvironment and enhance adaptive immune responses. Ultimately, our group aims to exploit the concept that successful cancer therapy is dependent upon an effective immune response. Surgery will remain an integral part of head and neck squamous cell carcinoma (HNSCC) treatment in the future, even as checkpoint inhibitors, co-stimulatory molecules, vaccines, adoptive T cell therapy and other novel agents enter clinical routine. Cytoreductive resection may provide an effective platform for immunotherapy and biomarker directed interventions to improve outcomes for patients with HNSCC.


Asunto(s)
Carcinoma de Células Escamosas/cirugía , Neoplasias de Cabeza y Cuello/cirugía , Inmunoterapia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Humanos
17.
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
18.
Clin Transl Immunology ; 5(4): e70, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27195113

RESUMEN

The tumor microenvironment of squamous cell carcinoma of the head and neck (SCCHN) has been shown to be immune suppressive. Therefore, strategies aimed at overcoming this issue could have a positive therapeutic impact. Hence, we investigated the expression of the known immune-modulatory proteins OX40, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in SCCHN on different T-cell subsets of tumor-infiltrating lymphocytes (TIL) to ascertain whether these proteins could potentially be targeted alone or in combination for future clinical trials. T cells from peripheral blood (PBL) and tumor were analyzed for the expression of OX40, PD-1 and CTLA-4 in 29 patients undergoing surgery. These proteins were all expressed significantly higher in T-cell subsets isolated from tumors compared with PBL of the same patient. OX40 expression was significantly greater in the TIL regulatory T-cell (Treg) population relative to conventional CD4 and CD8 TIL or the Treg isolated from PBL. PD-1 expression was increased in all T-cell subsets relative to PBL. CTLA-4 was also increased in all TIL subsets relative to blood, and similar to OX40, its highest level of expression was observed in the Treg TIL. The highest frequency of PD-1, CTLA-4 and OX40 triple-positive cells were found in the Treg population isolated from the tumor. We analyzed both human papilloma virus-positive and -negative patients and found similar levels and expression patterns of these two patient populations for all three proteins. These data suggest that there may be therapeutic advantages of targeting these pathways independently or in combination for patients with this disease.

19.
Oral Oncol ; 52: 1-10, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26614363

RESUMEN

OX40 is a member of the tumor necrosis factor (TNF) receptor family and a potent co-stimulatory pathway that when triggered can enhance T-cell memory, proliferation and anti-tumor activity in patients with metastatic cancer. Ongoing investigations at our institution have demonstrated that OX40 expressing T cells are found in abundance in the tumors of patients with advanced stage head and neck squamous cell carcinoma (HNSCC). This has led to the initiation of human clinical trials investigating OX40-directed therapy for patients with HNSCC in both the metastatic and curative setting. The purpose of this review is to explore what is known about OX40 signaling and discuss how this pathway potentially can be modulated to improve outcome for patients with HNSCC.


Asunto(s)
Carcinoma de Células Escamosas/inmunología , Neoplasias de Cabeza y Cuello/inmunología , Receptores OX40/inmunología , Linfocitos T/inmunología , Animales , Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Ratones , Receptor de Muerte Celular Programada 1/metabolismo , Receptores OX40/metabolismo , Linfocitos T/metabolismo , Microambiente Tumoral
20.
Cancer Immunol Res ; 3(5): 526-35, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25627655

RESUMEN

In preclinical tumor models, αOX40 therapy is often successful at treating small tumors, but is less effective once the tumors become large. For a tumor immunotherapy to be successful to cure large tumors, it will most likely require not only an agonist to boost effector T-cell function but also inhibitors of T-cell suppression. In this study, we show that combining αOX40 antibodies with an inhibitor of the TGFß receptor (SM16) synergizes to elicit complete regression of large established MCA205 and CT26 tumors. Evaluation of tumor-infiltrating T cells showed that SM16/αOX40 dual therapy resulted in an increase in proliferating granzyme B(+) CD8 T cells, which produced higher levels of IFNγ, compared with treatment with either agent alone. We also found that the dual treatment increased pSTAT3 expression in both CD4 and CD8 T cells isolated from tumors. Because others have published that STAT3 signaling is detrimental to T-cell function within the tumor microenvironment, we explored whether deletion of STAT3 in OX40-expressing cells would affect this potent combination therapy. Surprisingly, we found that deletion of STAT3 in OX40-expressing cells decreased the efficacy of this combination therapy, showing that the full therapeutic potential of this treatment depends on STAT3 signaling, most likely in the T cells of tumor-bearing mice.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias/metabolismo , Receptores OX40/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Animales , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos de Azabiciclo/administración & dosificación , Línea Celular Tumoral , Femenino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Receptores OX40/inmunología , Transducción de Señal
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