Oncotarget

Research Papers:

Axl inhibition induces the antitumor immune response which can be further potentiated by PD-1 blockade in the mouse cancer models

Zhiqiang Guo _, Yan Li, Dandan Zhang and Jiaying Ma

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Oncotarget. 2017; 8:89761-89774. https://doi.org/10.18632/oncotarget.21125

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Abstract

Zhiqiang Guo1, Yan Li2, Dandan Zhang1 and Jiaying Ma1

1Department of Gynecology and Obstetrics, Shengjing Hospital, China Medical University, ShenYang, China

2Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital of China Medical University, ShenYang, China

Correspondence to:

Zhiqiang Guo, email: zqg_cmu@163.com

Keywords: Axl, PD-1, immune checkpoint, CD103+ DC, R428

Received: June 23, 2017     Accepted: September 08, 2017     Published: September 21, 2017

ABSTRACT

Immune checkpoint blockers (ICB) have emerged as a promising new class of antitumor agents which significantly change the treatment landscape in a range of tumors; however, cancer patients benefited from ICB-based immunotherapy remains limited, scoring the need to explore the combination treatments with synergistic mechanisms of action. Axl receptor tyrosine kinase critically involves in the carcinogenesis of multiple cancers due to its dual roles in both promoting cancer invasion and metastasis and suppressing myeloid cell activation and function. Here, we found that Axl inhibition by tyrosine kinase inhibitors induces antitumor efficacy critically depending on immune effector mechanisms in two highly clinical relevant murine tumor models. Mechanistic investigation defined that Axl inhibition reprograms the immunological microenvironment leading to the increased proliferation, activation and effector function of tumor-infiltrating CD4+ and CD8+ T cells possibly through preferential accumulation and activation of CD103+ cross-presenting dendritic cells. More importantly, we show that Axl inhibition induces an adaptive immune resistance evidenced by unregulated PD-L1 expression on tumor cells and combined Axl inhibition with PD-1 blockade mounts a potent synergistic antitumor efficacy leading to tumor eradication. Thus, Axl-directed therapy in Axl expressing tumors could hold a great potential to subvert the innate and/or adaptive resistance to and broaden the coverage of population benefited from ICB-based immunotherapy.


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