Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion.
Nat Commun
; 11(1): 4520, 2020 09 09.
Article
em En
| MEDLINE
| ID: mdl-32908154
ABSTRACT
Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores Imunológicos
/
Colágeno
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Linfócitos T CD8-Positivos
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Resistencia a Medicamentos Antineoplásicos
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Antineoplásicos Imunológicos
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Adenocarcinoma de Pulmão
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article