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1.
Immunity ; 53(2): 335-352.e8, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32610077

RESUMO

Dendritic cells (DCs) are antigen-presenting cells controlling T cell activation. In humans, the diversity, ontogeny, and functional capabilities of DC subsets are not fully understood. Here, we identified circulating CD88-CD1c+CD163+ DCs (called DC3s) as immediate precursors of inflammatory CD88-CD14+CD1c+CD163+FcεRI+ DCs. DC3s develop via a specific pathway activated by GM-CSF, independent of cDC-restricted (CDP) and monocyte-restricted (cMoP) progenitors. Like classical DCs but unlike monocytes, DC3s drove activation of naive T cells. In vitro, DC3s displayed a distinctive ability to prime CD8+ T cells expressing a tissue homing signature and the epithelial homing alpha-E integrin (CD103) through transforming growth factor ß (TGF-ß) signaling. In vivo, DC3s infiltrated luminal breast cancer primary tumors, and DC3 infiltration correlated positively with CD8+CD103+CD69+ tissue-resident memory T cells. Together, these findings define DC3s as a lineage of inflammatory DCs endowed with a strong potential to regulate tumor immunity.


Assuntos
Antígenos CD1/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/citologia , Células Dendríticas/imunologia , Glicoproteínas/metabolismo , Cadeias alfa de Integrinas/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos NOD , Fator de Crescimento Transformador beta1/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo
2.
Oncoimmunology ; 12(1): 2225291, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37363103

RESUMO

Gallbladder cancer (GBC) is commonly diagnosed at late stages when conventional treatments achieve only modest clinical benefit. Therefore, effective treatments for advanced GBC are needed. In this context, the administration of T cells genetically engineered with chimeric antigen receptors (CAR) has shown remarkable results in hematological cancers and is being extensively studied for solid tumors. Interestingly, GBC tumors express canonical tumor-associated antigens, including the carcinoembryonic antigen (CEA). However, the potential of CEA as a relevant antigen in GBC to be targeted by CAR-T cell-based immunotherapy has not been addressed. Here we show that CEA was expressed in 88% of GBC tumors, with higher levels associated with advanced disease stages. CAR-T cells specifically recognized plate-bound CEA as evidenced by up-regulation of 4-1BB, CD69 and PD-1, and production of effector cytokines IFN-γ and TNF-α. In addition, CD8+ CAR-T cells up-regulated the cytotoxic molecules granzyme B and perforin. Interestingly, CAR-T cell activation occurred even in the presence of PD-L1. Consistent with these results, CAR-T cells efficiently recognized GBC cell lines expressing CEA and PD-L1, but not a CEA-negative cell line. Furthermore, CAR-T cells exhibited in vitro cytotoxicity and reduced in vivo tumor growth of GB-d1 cells. In summary, we demonstrate that CEA represents a relevant antigen for GBC that can be targeted by CAR-T cells at the preclinical level. This study warrants further development of the adoptive transfer of CEA-specific CAR-T cells as a potential immunotherapy for GBC.


Assuntos
Neoplasias da Vesícula Biliar , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/genética , Antígeno Carcinoembrionário/genética , Imunoterapia Adotiva/métodos , Antígeno B7-H1 , Neoplasias da Vesícula Biliar/terapia , Imunoterapia , Linfócitos T
3.
Oncoimmunology ; 7(7): e1442163, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900048

RESUMO

Memory CD8+ T cell responses have the potential to mediate long-lasting protection against cancers. Resident memory CD8+ T (Trm) cells stably reside in non-lymphoid tissues and mediate superior innate and adaptive immunity against pathogens. Emerging evidence indicates that Trm cells develop in human solid cancers and play a key role in controlling tumor growth. However, the specific contribution of Trm cells to anti-tumor immunity is incompletely understood. Moreover, clinically applicable vaccination strategies that efficiently establish Trm cell responses remain largely unexplored and are expected to strongly protect against tumors. Here we demonstrated that a single intradermal administration of gene- or protein-based vaccines efficiently induces specific Trm cell responses against models of tumor-specific and self-antigens, which accumulated in vaccinated and distant non-vaccinated skin. Vaccination-induced Trm cells were largely resistant to in vivo intravascular staining and antibody-dependent depletion. Intradermal, but not intraperitoneal vaccination, generated memory precursors expressing skin-homing molecules in circulation and Trm cells in skin. Interestingly, vaccination-induced Trm cell responses strongly suppressed the growth of B16F10 melanoma, independently of circulating memory CD8+ T cells, and were able to infiltrate tumors. This work highlights the therapeutic potential of vaccination-induced Trm cell responses to achieve potent protection against skin malignancies.

4.
Rev. ecuat. pediatr ; 20(2): 47-50, diciembre 2019.
Artigo em Espanhol | LILACS | ID: biblio-1116485

RESUMO

La osteomielitis de cadera es una infección poco frecuente en la edad pediátrica, que suele afectar el ilion, el isquion, el pubis y el acetábulo. Su diagnóstico es complejo y se retrasa debido a la localización profunda del foco infeccioso por lo que amerita la realización de una resonancia magnética para su diagnóstico certero. Este artículo presenta el caso clínico de un paciente de 5 años con dolor en la cadera derecha posterior a un traumatismo. El paciente fue diagnosticado de osteomielitis pélvica en el Hospital General Enrique Garcés donde recibió tratamiento antibiótico intravenoso por 30 días, con resultados satisfactorios. En conclusión, si bien la osteomielitis pélvica es una infección inusual en pediatría, es una enfermedad importante por las complicaciones que puede ocasionar si no se trata a tiempo por lo que es necesario comenzar el tratamiento de inmediato, para lograr resultados clínicos satisfactorios.


Osteomyelitis of the hip is a rare infection in children, which usually affects the ilium, ischium, pubis and acetabulum. Its diagnosis is complex and it is delayed due to the deep location of the infection, which requires a magnetic resonance imaging for its accurate diagnosis. This article presents the clinical case of a 5-year-old patient with pain in the right hip after trauma. The patient was diagnosed with pelvic osteomyelitis at the Enrique Garcés General Hospital where he received intravenous antibiotic treatment for 30 days, with satisfactory results. In conclusion, although pelvic osteomyelitis is an unusual infection in pediatrics, it is an important disease due to the complications it can cause if it is not treated in time, so it is necessary to begin treatment immediately, in order to achieve satisfactory clinical results.


Assuntos
Humanos , Masculino , Pré-Escolar , Osteomielite , Quadril , Antibacterianos , Pediatria , Terapêutica , Ferimentos e Lesões
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