KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinomaReportar como inadecuado




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Cancer Immunology, Immunotherapy

pp 1–13

First Online: 27 April 2017Received: 24 July 2016Accepted: 18 April 2017DOI: 10.1007-s00262-017-2005-z

Cite this article as: Chen, N., Fang, W., Lin, Z. et al. Cancer Immunol Immunother 2017. doi:10.1007-s00262-017-2005-z

Abstract

It was reported that PD-L1 expression was correlated with genetic alterations. Whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog KRAS in non-small-cell lung cancer NSCLC and the underlying molecular mechanism were largely unknown. In this study, we investigated the correlation between PD-L1 expression and KRAS mutation and the functional significance of PD-1-PD-L1 blockade in KRAS-mutant lung adenocarcinoma. We found that PD-L1 expression was associated with KRAS mutation both in the human lung adenocarcinoma cell lines and tissues. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling. We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by anti-PD-1 antibody Pembrolizumab or ERK inhibitor. PD-1 blocker or ERK inhibitor could recover the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, Pembrolizumab combined with ERK inhibitor did not show synergistic effect on killing tumor cells in co-culture system. Our study demonstrated that KRAS mutation could induce PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Blockade of PD-1-PD-L1 pathway may be a promising therapeutic strategy for human KRAS-mutant lung adenocarcinoma.

KeywordsKRAS PD-L1 PD-1 Lung adenocarcinoma AbbreviationsALKAnaplastic lymphoma kinase

CSTCell signaling technology

CTLA-4Cytotoxic T lymphocyte associated antigen-4

DC-CIKDendritic cells and cytokine-induced killer cells

EGFREpidermal growth factor receptor

EML4Echinoderm microtubule associated protein like 4

KRASKirsten rat sarcoma viral oncogene homolog

NSCLCNon-small-cell lung cancer

PD-1Programmed death-1 receptor

PD-L1Programmed death ligand 1

TKIsTyrosine kinase inhibitors

Electronic supplementary materialThe online version of this article doi:10.1007-s00262-017-2005-z contains supplementary material, which is available to authorized users.

The authors, Nan Chen, Wenfeng Fang, and Zhong Lin contributed equally to this work.





Autor: Nan Chen - Wenfeng Fang - Zhong Lin - Peijian Peng - Juan Wang - Jianhua Zhan - Shaodong Hong - Jiaxing Huang - Lin Liu -

Fuente: https://link.springer.com/







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