Combination PD-1 and PD-L1 Blockade Promotes Durable Neoantigen-Specific T Cell-Mediated Immunity in Pancreatic Ductal Adenocarcinoma.
Cell Rep
; 28(8): 2140-2155.e6, 2019 08 20.
Article
em En
| MEDLINE
| ID: mdl-31433988
ABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptideMHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhances systemic T cell expansion and induces objective responses that require systemic T cells. However, tumor escape variants defective in IFNγ-inducible Tap1 and MHC class I cell surface expression ultimately emerge. Combination PD-1 + PD-L1 blockade synergizes therapeutically by increasing intratumoral KLRG1+Lag3-TNFα+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recurrence, thereby prolonging animal survival. Our studies support that PD-1 and PD-L1 are relevant immune checkpoints in PDA and identify a combination for clinical testing in those patients with neoantigen-specific T cells.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Linfócitos T
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Carcinoma Ductal Pancreático
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Antígeno B7-H1
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Receptor de Morte Celular Programada 1
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Imunidade Celular
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Imunoterapia
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Antígenos de Neoplasias
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article