PD-1/PD-L1 immune checkpoint and p53 loss facilitate tumor progression in activated B-cell diffuse large B-cell lymphomas.
Blood
; 133(22): 2401-2412, 2019 05 30.
Article
em En
| MEDLINE
| ID: mdl-30975638
ABSTRACT
Refractory or relapsed diffuse large B-cell lymphoma (DLBCL) often associates with the activated B-cell-like (ABC) subtype and genetic alterations that drive constitutive NF-κB activation and impair B-cell terminal differentiation. Here, we show that DNA damage response by p53 is a central mechanism suppressing the pathogenic cooperation of IKK2ca-enforced canonical NF-κB and impaired differentiation resulting from Blimp1 loss in ABC-DLBCL lymphomagenesis. We provide evidences that the interplay between these genetic alterations and the tumor microenvironment select for additional molecular addictions that promote lymphoma progression, including aberrant coexpression of FOXP1 and the B-cell mutagenic enzyme activation-induced deaminase, and immune evasion through major histocompatibility complex class II downregulation, PD-L1 upregulation, and T-cell exhaustion. Consistently, PD-1 blockade cooperated with anti-CD20-mediated B-cell cytotoxicity, promoting extended T-cell reactivation and antitumor specificity that improved long-term overall survival in mice. Our data support a pathogenic cooperation among NF-κB-driven prosurvival, genetic instability, and immune evasion mechanisms in DLBCL and provide preclinical proof of concept for including PD-1/PD-L1 blockade in combinatorial immunotherapy for ABC-DLBCL.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
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Ativação Linfocitária
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Regulação Neoplásica da Expressão Gênica
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Proteína Supressora de Tumor p53
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Linfoma Difuso de Grandes Células B
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Evasão Tumoral
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Antígeno B7-H1
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Receptor de Morte Celular Programada 1
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article