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1.
Mol Ther ; 31(7): 2120-2131, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-37081789

RESUMEN

IL-17-producing antigen-specific human T cells elicit potent antitumor activity in mice. Yet, refinement of this approach is needed to position it for clinical use. While activation signal strength regulates IL-17 production by CD4+ T cells, the degree to which T cell antigen receptor (TCR) and costimulation signal strength influences Th17 immunity remains unknown. We discovered that decreasing TCR/costimulation signal strength by incremental reduction of αCD3/costimulation beads progressively altered Th17 phenotype. Moreover, Th17 cells stimulated with αCD3/inducible costimulator (ICOS) beads produced more IL-17A, IFNγ, IL-2, and IL-22 than those stimulated with αCD3/CD28 beads. Compared with Th17 cells stimulated with the standard, strong signal strength (three beads per T cell), Th17 cells propagated with 30-fold fewer αCD3/ICOS beads were less reliant on glucose and favored the central carbon pathway for bioenergetics, marked by abundant intracellular phosphoenolpyruvate (PEP). Importantly, Th17 cells stimulated with weak αCD3/ICOS beads and redirected with a chimeric antigen receptor that recognizes mesothelin were more effective at clearing human mesothelioma. Less effective CAR Th17 cells generated with high αCD3/ICOS beads were rescued by overexpressing phosphoenolpyruvate carboxykinase 1 (PCK1), a PEP regulator. Thus, Th17 therapy can be improved by using fewer activation beads during manufacturing, a finding that is cost effective and directly translatable to patients.


Asunto(s)
Proteína Coestimuladora de Linfocitos T Inducibles , Interleucina-17 , Receptores Quiméricos de Antígenos , Animales , Humanos , Ratones , Antígenos CD28/genética , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Interleucina-17/metabolismo , Activación de Linfocitos , Fosfoenolpiruvato/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Transducción de Señal , Células Th17/metabolismo
2.
J Immunol Res Ther ; 2(1): 68-79, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28825053

RESUMEN

Adoptive T cell transfer (ACT) can mediate objective responses in patients with advanced malignancies. There have been major advances in this field, including the optimization of the ex vivo generation of tumor-reactive lymphocytes to ample numbers for effective ACT therapy via the use of natural and artificial antigen presenting cells (APCs). Herein we review the basic properties of APCs and how they have been manufactured through the years to augment vaccine and T cell-based cancer therapies. We then discuss how these novel APCs impact the function and memory properties of T cells. Finally, we propose new ways to synthesize aAPCs to augment the therapeutic effectiveness of antitumor T cells for ACT therapy.

3.
Nat Commun ; 8(1): 1961, 2017 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-29213079

RESUMEN

CD8+ T lymphocytes mediate potent immune responses against tumor, but the role of human CD4+ T cell subsets in cancer immunotherapy remains ill-defined. Herein, we exhibit that CD26 identifies three T helper subsets with distinct immunological properties in both healthy individuals and cancer patients. Although CD26neg T cells possess a regulatory phenotype, CD26int T cells are mainly naive and CD26high T cells appear terminally differentiated and exhausted. Paradoxically, CD26high T cells persist in and regress multiple solid tumors following adoptive cell transfer. Further analysis revealed that CD26high cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (ß-catenin and Lef1). These properties license CD26high T cells with a natural capacity to traffic to, regress and survive in solid tumors. Collectively, these findings identify CD4+ T cell subsets with properties critical for improving cancer immunotherapy.


Asunto(s)
Dipeptidil Peptidasa 4/inmunología , Dipeptidil Peptidasa 4/metabolismo , Neoplasias/inmunología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Animales , Apoptosis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Movimiento Celular/inmunología , Citocinas/inmunología , Dipeptidil Peptidasa 4/sangre , Modelos Animales de Enfermedad , Granzimas , Humanos , Inmunidad , Memoria Inmunológica , Inmunoterapia , Factor de Unión 1 al Potenciador Linfoide , Proteína 1 de la Membrana Asociada a los Lisosomas/inmunología , Melanoma/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias/patología , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-kit , Linfocitos T Colaboradores-Inductores/inmunología , beta Catenina
4.
Front Immunol ; 8: 1221, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29033940

RESUMEN

Phosphatidylinositol-3-kinase p110δ (PI3Kδ) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells. Yet, little is known about the direct impact of PI3Kδ blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110δ inactivation via CAL-101 on murine and human CD8+ T cells that promotes a strong undifferentiated phenotype (elevated CD62L/CCR7, CD127, and Tcf7). These CAL-101 T cells also persisted longer after transfer into tumor bearing mice in both the murine syngeneic and human xenograft mouse models. The less differentiated phenotype and improved engraftment of CAL-101 T cells resulted in stronger antitumor immunity compared to traditionally expanded CD8+ T cells in both tumor models. Thus, this report describes a novel direct enhancement of CD8+ T cells by a p110δ inhibitor that leads to markedly improved tumor regression. This finding has significant implications to improve outcomes from next generation cancer immunotherapies.

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