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1.
Sci Adv ; 9(49): eadj6174, 2023 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-38055824

RESUMO

Clonotypic αß T cell responses to cargoes presented by major histocompatibility complex (MHC), MR1, or CD1 proteins underpin adaptive immunity. Those responses are mostly mediated by complementarity-determining region 3 motifs created by quasi-random T cell receptor (TCR) gene rearrangements, with diversity being highest for TCRγδ. Nonetheless, TCRγδ also displays nonclonotypic innate responsiveness following engagement of germline-encoded Vγ-specific residues by butyrophilin (BTN) or BTN-like (BTNL) proteins that uniquely mediate γδ T cell subset selection. We now report that nonclonotypic TCR engagement likewise induces distinct phenotypes in TCRαß+ cells. Specifically, antibodies to germline-encoded human TCRVß motifs consistently activated naïve or memory T cells toward core states distinct from those induced by anti-CD3 or superantigens and from others commonly reported. Those states combined selective proliferation and effector function with activation-induced inhibitory receptors and memory differentiation. Thus, nonclonotypic TCRVß targeting broadens our perspectives on human T cell response modes and might offer ways to induce clinically beneficial phenotypes in defined T cell subsets.


Assuntos
Receptores de Antígenos de Linfócitos T alfa-beta , Receptores de Antígenos de Linfócitos T gama-delta , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Subpopulações de Linfócitos T , Butirofilinas/genética , Butirofilinas/metabolismo , Fenótipo , Imunoterapia
2.
Sci Transl Med ; 15(724): eadi0258, 2023 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-38019931

RESUMO

Despite the success of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) inhibitors in treating solid tumors, only a proportion of patients respond. Here, we describe a first-in-class bifunctional therapeutic molecule, STAR0602, that comprises an antibody targeting germline Vß6 and Vß10 T cell receptors (TCRs) fused to human interleukin-2 (IL-2) and simultaneously engages a nonclonal mode of TCR activation with costimulation to promote activation and expansion of αß T cell subsets expressing distinct variable ß (Vß) TCR chains. In solution, STAR0602 binds IL-2 receptors in cis with Vß6/Vß10 TCRs on the same T cell, promoting expansion of human Vß6 and Vß10 CD4+ and CD8+ T cells that acquire an atypical central memory phenotype. Monotherapy with a mouse surrogate molecule induced durable tumor regression across six murine solid tumor models, including several refractory to anti-PD-1. Analysis of murine tumor-infiltrating lymphocyte (TIL) transcriptomes revealed that expanded Vß T cells acquired a distinct effector memory phenotype with suppression of genes associated with T cell exhaustion and TCR signaling repression. Sequencing of TIL TCRs also revealed an increased T cell repertoire diversity within targeted Vß T cell subsets, suggesting clonal revival of tumor T cell responses. These immunological and antitumor effects in mice were recapitulated in studies of STAR0602 in nonhuman primates and human ex vivo models, wherein STAR0602 boosted human antigen-specific T cell responses and killing of tumor organoids. Thus, STAR0602 represents a distinct class of T cell-activating molecules with the potential to deliver enhanced antitumor activity in checkpoint inhibitor-refractory settings.


Assuntos
Neoplasias , Receptores de Antígenos de Linfócitos T alfa-beta , Humanos , Animais , Camundongos , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Anticorpos/farmacologia
3.
EMBO J ; 25(12): 2686-97, 2006 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-16763560

RESUMO

Simultaneous ablation of the two known activators of plasminogen (Plg), urokinase-type (uPA) and the tissue-type (tPA), results in a substantial delay in skin wound healing. However, wound closure and epidermal re-epithelialization are significantly less impaired in uPA;tPA double-deficient mice than in Plg-deficient mice. Skin wounds in uPA;tPA-deficient mice treated with the broad-spectrum matrix metalloproteinase (MMP) inhibitor galardin (N-[(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide) eventually heal, whereas skin wounds in galardin-treated Plg-deficient mice do not heal. Furthermore, plasmin is biochemically detectable in wound extracts from uPA;tPA double-deficient mice. In vivo administration of a plasma kallikrein (pKal)-selective form of the serine protease inhibitor ecotin exacerbates the healing impairment of uPA;tPA double-deficient wounds to a degree indistinguishable from that observed in Plg-deficient mice, and completely blocks the activity of pKal, but not uPA and tPA in wound extracts. These findings demonstrate that an additional plasminogen activator provides sufficient plasmin activity to sustain the healing process albeit at decreased speed in the absence of uPA, tPA and galardin-sensitive MMPs and suggest that pKal plays a role in plasmin generation.


Assuntos
Plasminogênio/metabolismo , Ativador de Plasminogênio Tecidual/deficiência , Ativador de Plasminogênio Tipo Uroquinase/deficiência , Cicatrização/fisiologia , Animais , Dipeptídeos/farmacologia , Ativação Enzimática , Fibrinolisina/metabolismo , Fibrinólise , Queratinócitos/citologia , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Calicreína Plasmática/metabolismo , Inibidores de Serina Proteinase/farmacologia , Pele/citologia , Pele/patologia , Fatores de Tempo , Ativador de Plasminogênio Tecidual/genética , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Cicatrização/efeitos dos fármacos
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