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1.
Sci Rep ; 13(1): 463, 2023 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-36627334

RESUMEN

Tumor-derived extracellular vesicles (EVs) are active contributors in metastasis and immunosuppression in tumor microenvironment. At least some of the EVs carry tumor surface molecules such as tumor-associated antigens (TAAs) and/or checkpoint inhibitors, and potentially could interact with T cells or CAR T cells. Upon contact with T cells, EVs could alter their phenotype and functions by triggering signaling through TCR or CAR reprogramming them to escape immune response. We hypothesize that EVs that possess TAA on the surface will probably interact with CAR T cells which can recognize and bind corresponding TAA. This interaction between EVs and CAR T cells may change the outcome of CAR T-based cancer immunotherapy since it should affect CAR T cells. Also, EVs could serve as adjuvants and antigenic components of antitumor vaccines. Herein, we isolated EVs from B cell precursor leukemia cell line (pre-B ALL) Nalm-6 and demonstrated that recognition and binding of CD19+EVs with CD19-CAR T cells strongly depends on the presence of CD19 antigen. CD19+EVs induce secretion of pro-inflammatory cytokines (IL-2 and IFN-y) and upregulated transcription of activation-related genes (IFNG, IFNGR1, FASLG, IL2) in CD19-CAR T cells. Tumor necrosis factor receptor superfamily (TNFRSF4 and TNFRSF9) and T-cell exhaustion markers (CTLA4, LAG3, TIM3 and PDCD1LG2) were also upregulated in CD19-CAR T cells after incubation with CD19+EVs. Long-term cultivation of CD19+ or PD-L1+EVs with CD19-CAR T cells led to increased terminal differentiation and functional exhaustion according to elevated expression of PD-1, TIGIT, CD57. In summary, our results suggest that chronic exposure of CD19-CAR T cells to CD19+EVs mediates activation and systemic exhaustion in antigen-specific manner, and this negative effect is accompanied by the impaired cytotoxic activity in vitro.


Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Humanos , Inmunoterapia Adoptiva/métodos , Linfocitos T , Citocinas/metabolismo , Antineoplásicos/metabolismo , Antígenos CD19/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Complejo CD3/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Microambiente Tumoral
2.
Front Mol Biosci ; 8: 745286, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34722633

RESUMEN

CAR-T cell therapy is the most advanced way to treat therapy resistant hematologic cancers, in particular B cell lymphomas and leukemias, with high efficiency. Donor T cells equipped ex vivo with chimeric receptor recognize target tumor cells and kill them using lytic granules. CAR-T cells that recognize CD19 marker of B cells (CD19 CAR-T) are considered the gold standard of CAR-T therapy and are approved by FDA. But in some cases, CD19 CAR-T cell therapy fails due to immune suppressive microenvironment. It is shown that tumor cells upregulate expression of PD-L1 surface molecule that binds and increases level and signal provided by PD-1 receptor on the surface of therapeutic CAR-T cells. Induction of this negative signaling results in functional impairment of cytotoxic program in CAR-T cells. Multiple attempts were made to block PD-1 signaling by reducing binding or surface level of PD-1 in CAR-T cells by various means. In this study we co-expressed CD19-CAR with PD-1-specific VHH domain of anti-PD-1 nanobody to block PD-1/PD-L1 signaling in CD19 CAR-T cells. Unexpectedly, despite increased activation of CAR-T cells with low level of PD-1, these T cells had reduced survival and diminished cytotoxicity. Functional impairment caused by disrupted PD-1 signaling was accompanied by faster maturation and upregulation of exhaustion marker TIGIT in CAR-T cells. We conclude that PD-1 in addition to its direct negative effect on CAR-induced signaling is required for attenuation of strong stimulation leading to cell death and functional exhaustion. These observations suggest that PD-1 downregulation should not be considered as the way to improve the quality of therapeutic CAR-T cells.

3.
Acta Naturae ; 11(4): 33-41, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31993233

RESUMEN

In this article, we present a comprehensive, updated, and elucidative review of the current knowledge on the function played by tumor-derived vesicles (TDVs) in the crosstalk between tumor and immune cells. Characterization of the structure, biogenesis, and the major functions of TDVs is reported. The review focuses on particular ways of suppression or activation of CD4+/CD8+ T cells by tumor-derived vesicles. Tumor-derived vesicles play an important role in the suppression of antitumor immunity. During the last 15 years, vesicle research has elucidated and improved our knowledge about the role of the vesicles in intercellular communication. Nevertheless, there are still blinds spots concerning vesicle heterogeneity and isolation methods, their uptake by target cells, and the role of mRNA in T-cell transformation or suppression. Along with the substantial progress in understanding of the role of tumor-derived vesicles in intercellular communication, novel antitumor therapy strategies based on vesicle inhibition in a tumor microenvironment are likely to appear very soon.

4.
Bull Exp Biol Med ; 165(3): 386-389, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30003423

RESUMEN

Death receptor 5 (DR5) is a promising target for antitumor therapy due to its high expression on different tumor cells. Resistance of various tumor cells against TRAIL, a natural ligand for the death receptors, reduces its therapeutic potential and prompts the search for novel agonists at these receptors. Previous screening across the combinatorial peptide library yielded a peptide sequence KVVLTHR that specifically binds DR5. Incorporation of this sequence into TNFα resulted in binding DR5 with mutant protein TNFα-mut and appearance of cytotoxicity against lymphoma cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Linfocitos/efectos de los fármacos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Factor de Necrosis Tumoral alfa/genética , Secuencia de Aminoácidos , Apoptosis/genética , Sitios de Unión , Línea Celular Tumoral , Clonación Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Humanos , Linfocitos/metabolismo , Linfocitos/patología , Modelos Moleculares , Mutación , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/antagonistas & inhibidores , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/química , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/química , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF/química , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología
5.
Acta Naturae ; 9(3): 55-63, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29104776

RESUMEN

This article offers a detailed review of the current approaches to anticancer therapy that target the death receptors of malignant cells. Here, we provide a comprehensive overview of the structure and function of death receptors and their ligands, describe the current and latest trends in the development of death receptor agonists, and perform their comparative analysis. In addition, we discuss the DR4 and DR5 agonistic antibodies that are being evaluated at various stages of clinical trials. Finally, we conclude by stating that death receptor agonists may be improved through increasing their stability, solubility, and elimination half-life, as well as by overcoming the resistance of tumor cells. What's more, effective application of these antibodies requires a more detailed study of their use in combination with other anticancer agents.

6.
Bull Exp Biol Med ; 163(3): 381-384, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28744632

RESUMEN

Death receptors, in particular DR5, are highly attractive targets of antitumor therapy. The major limitation to application of natural death receptor ligands (TRAIL) is their non-specific cytotoxicity against normal cells. Since TRAIL can also bind decoy receptors (DcR) and prevent induction of apoptosis, the search for new DR-specific ligands is a topical issue. In the present study, we used combinatorial phage display peptide libraries to select a panel of DR5-binding amino acid sequences. A comparative analysis of the selected peptides enabled identification of the consensus sequence responsible for binding to DR5. Integration of this motif into polypeptide cytotoxic agents may provide targeted elimination of malignantly transformed cells.


Asunto(s)
Fragmentos Fc de Inmunoglobulinas/química , Biblioteca de Péptidos , Péptidos/química , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/química , Proteínas Recombinantes de Fusión/química , Secuencias de Aminoácidos , Animales , Sitios de Unión , Expresión Génica , Células HEK293 , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Separación Inmunomagnética/métodos , Ligandos , Ratones , Modelos Moleculares , Péptidos/genética , Péptidos/inmunología , Plásmidos/química , Plásmidos/metabolismo , Unión Proteica , Estructura Secundaria de Proteína , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Transfección
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