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1.
Cell ; 170(5): 927-938.e20, 2017 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-28841418

RESUMO

We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8+ and CD4+ T cells and exhibited oligoclonal expansion of specific T cell subsets. We also detected CD8+ T cell reactivity against predicted neoepitopes after isolation of cells from a blood sample taken almost 3 years after the tumors were resected. These findings suggest that multiple distinct tumor immune microenvironments co-exist within a single individual and may explain in part the heterogeneous fates of metastatic lesions often observed in the clinic post-therapy. VIDEO ABSTRACT.


Assuntos
Cistadenocarcinoma Seroso/patologia , Metástase Neoplásica/imunologia , Neoplasias Ovarianas/patologia , Microambiente Tumoral , Antígenos de Neoplasias/imunologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/terapia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Metástase Neoplásica/genética , Metástase Neoplásica/terapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Linfócitos T/imunologia , Transcriptoma
2.
Br J Haematol ; 199(3): 366-370, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35892294

RESUMO

Outcomes remain poor for patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). While chimeric antigen receptor (CAR) T-cell therapy has revolutionised treatment, a significant proportion of patients relapse or fail to respond. Odronextamab is a CD20 × CD3 bispecific antibody that has demonstrated durable responses and a manageable safety profile in patients with R/R B-NHL in a first-in-human trial (NCT02290951). Here, we document two patients with diffuse large B-cell lymphoma refractory to CART-cell therapy. Both achieved complete responses that remain ongoing for ≥2 years following odronextamab. Neither patient experienced Grade ≥3 cytokine release syndrome or Grade ≥3 neurological adverse events during treatment.


Assuntos
Anticorpos Biespecíficos , Antineoplásicos , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/uso terapêutico , Antígenos CD19 , Recidiva Local de Neoplasia/patologia , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Folicular/etiologia , Síndrome da Liberação de Citocina , Terapia Baseada em Transplante de Células e Tecidos , Receptores de Antígenos de Linfócitos T/genética
3.
Immunity ; 38(4): 818-30, 2013 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-23562160

RESUMO

In comparison to murine dendritic cells (DCs), less is known about the function of human DCs in tissues. Here, we analyzed, by using lung tissues from humans and humanized mice, the role of human CD1c(+) and CD141(+) DCs in determining the type of CD8(+) T cell immunity generated to live-attenuated influenza virus (LAIV) vaccine. We found that both lung DC subsets acquired influenza antigens in vivo and expanded specific cytotoxic CD8(+) T cells in vitro. However, lung-tissue-resident CD1c(+) DCs, but not CD141(+) DCs, were able to drive CD103 expression on CD8(+) T cells and promoted CD8(+) T cell accumulation in lung epithelia in vitro and in vivo. CD1c(+) DCs induction of CD103 expression was dependent on membrane-bound cytokine TGF-ß1. Thus, CD1c(+) and CD141(+) DCs generate CD8(+) T cells with different properties, and CD1c(+) DCs specialize in the regulation of mucosal CD8(+) T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Pulmão/imunologia , Subpopulações de Linfócitos T/imunologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Antígenos Virais/imunologia , Diferenciação Celular , Células Cultivadas , Citotoxicidade Imunológica , Glicoproteínas/metabolismo , Humanos , Imunidade nas Mucosas , Memória Imunológica , Vacinas contra Influenza/imunologia , Cadeias alfa de Integrinas/metabolismo , Pulmão/virologia , Ativação Linfocitária , Camundongos , Camundongos SCID , Análise em Microsséries
4.
Sci Rep ; 13(1): 8452, 2023 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-37231180

RESUMO

Identifying epitopes that T cells respond to is critical for understanding T cell-mediated immunity. Traditional multimer and other single cell assays often require large blood volumes and/or expensive HLA-specific reagents and provide limited phenotypic and functional information. Here, we present the Rapid TCR:Epitope Ranker (RAPTER) assay, a single cell RNA sequencing (scRNA-SEQ) method that uses primary human T cells and antigen presenting cells (APCs) to assess functional T cell reactivity. Using hash-tag oligonucleotide (HTO) coding and T cell activation-induced markers (AIM), RAPTER defines paired epitope specificity and TCR sequence and can include RNA- and protein-level T cell phenotype information. We demonstrate that RAPTER identified specific reactivities to viral and tumor antigens at sensitivities as low as 0.15% of total CD8+ T cells, and deconvoluted low-frequency circulating HPV16-specific T cell clones from a cervical cancer patient. The specificities of TCRs identified by RAPTER for MART1, EBV, and influenza epitopes were functionally confirmed in vitro. In summary, RAPTER identifies low-frequency T cell reactivities using primary cells from low blood volumes, and the resulting paired TCR:ligand information can directly enable immunogenic antigen selection from limited patient samples for vaccine epitope inclusion, antigen-specific TCR tracking, and TCR cloning for further therapeutic development.


Assuntos
Linfócitos T CD8-Positivos , Epitopos de Linfócito T , Humanos , Receptores de Antígenos de Linfócitos T/genética , Membrana Celular
5.
Sci Transl Med ; 14(649): eaba4380, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35704596

RESUMO

The majority of JAK2V617F-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-terminal mutant fragment (CALRMUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT-specific T cells are rare in patients with CALRMUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALRMUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are underrepresented in patients with CALRMUT MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALRMUT MPN would not efficiently respond to a CALRMUT fragment cancer vaccine but would when immunized with a modified CALRMUT heteroclitic peptide vaccine approach. We found that heteroclitic CALRMUT peptides specifically designed for the MHC-I alleles of patients with CALRMUT MPN efficiently elicited a CALRMUT cross-reactive CD8+ T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALRMUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8+ T cell response to the CALRMUT fragment upon immunization with a CALRMUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide-based cancer vaccines in patients with CALRMUT MPN.


Assuntos
Vacinas Anticâncer , Transtornos Mieloproliferativos , Neoplasias , Animais , Calreticulina/genética , Humanos , Janus Quinase 2/genética , Complexo Principal de Histocompatibilidade , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Transtornos Mieloproliferativos/genética , Neoplasias/genética , Peptídeos , Vacinas de Subunidades Antigênicas
6.
Nat Commun ; 11(1): 4011, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782249

RESUMO

Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.


Assuntos
Cinurenina/imunologia , Macrófagos/imunologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Tolerância Imunológica , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral
7.
Curr Protoc Cell Biol ; Chapter 3: Unit 3.40, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21154551

RESUMO

Highly conserved during evolution, the ribosome is the central effector of protein synthesis. In mammalian cells, the ribosome is a macromolecular complex composed of four different ribosomal RNAs (rRNA) and about 80 ribosomal proteins. Requiring more than 200 factors, ribosome biogenesis is a highly complex process that takes place mainly within the nucleoli of eukaryotic cells. Crystallographic data suggest that the ribosome is a ribozyme, in which the rRNA catalyses the peptide bond formation and ensures quality control of the translation. Ribosomal proteins are involved in this molecular mechanism; nonetheless, their role is still not fully characterized. Recent studies suggest that ribosomes themselves and/or the mechanisms underlying their synthesis, processing, and assembly play a key role in the establishment and progression of several human pathologies. The protocol described here is simple, efficient, and robust, and allows one to purify high-quality ribosomes from human cultured cell lines. Ribosomes purified with this protocol are adequate for most of the subsequent analyses of their RNA and protein content.


Assuntos
Fracionamento Celular/métodos , Ribossomos/metabolismo , Linhagem Celular , Humanos , Biossíntese de Proteínas , Ribossomos/genética
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