iRGD synergizes with PD-1 knockout immunotherapy by enhancing lymphocyte infiltration in gastric cancer

Naiqing Ding, Zhengyun Zou, Huizi Sha, Shu Su, Hanqing Qian, Fanyan Meng, Fangjun Chen, Shiyao Du, Shujuan Zhou, Hong Chen, Lianru Zhang, Ju Yang, Jia Wei () and Baorui Liu ()
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Naiqing Ding: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Zhengyun Zou: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Huizi Sha: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Shu Su: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Hanqing Qian: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Fanyan Meng: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Fangjun Chen: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Shiyao Du: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Shujuan Zhou: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Hong Chen: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Lianru Zhang: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Ju Yang: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Jia Wei: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University
Baorui Liu: Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract Poor infiltration of activated lymphocytes into tumors represents a fundamental factor limiting the therapeutic effect of adoptive cell immunotherapy. A tumor-penetrating peptide, iRGD, has been widely used to deliver drugs into tumor tissues. In this study, we demonstrate for the first time that iRGD could also facilitate the infiltration of lymphocytes in both 3D tumor spheroids and several xenograft mouse models. In addition, combining iRGD modification with PD-1 knockout lymphocytes reveals a superior anti-tumor efficiency. Mechanistic studies demonstrate that the binding of iRGD to neuropilin-1 results in tyrosine phosphorylation of the endothelial barrier regulator VE-cadherin, which plays a role in the opening of endothelial cell contacts and the promotion of transendothelial lymphocyte migration. In summary, these results demonstrate that iRGD modification could promote tumor-specific lymphocyte infiltration, and thereby overcome the bottleneck associated with adoptive immune cell therapy in solid tumors.

Date: 2019
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DOI: 10.1038/s41467-019-09296-6

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