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

• Published in: Nature communications Vol. 10; no. 1; p. 1336
• Main Authors: Ding, Naiqing, Zou, Zhengyun, Sha, Huizi, Su, Shu, Qian, Hanqing, Meng, Fanyan, Chen, Fangjun, Du, Shiyao, Zhou, Shujuan, Chen, Hong, Zhang, Lianru, Yang, Ju, Wei, Jia, Liu, Baorui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.03.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/51; 14/1; 14/19; 14/34; 14/63; 42/109; 59/5; 59/57; 631/67; 631/67/1059/2325; 631/67/1504; 631/67/580; 64/60; 82/58; 82/6; Animal models; Animals; Antigens, CD - metabolism; Cadherins; Cadherins - metabolism; Cell Line, Tumor; Drug delivery systems; Endothelial cells; Gastric cancer; Gene Knockout Techniques; Human Umbilical Vein Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Immune system; Immunosuppressive agents; Immunotherapy; Infiltration; Leukocyte migration; Lymphocytes; Lymphocytes - immunology; Male; Metastases; Mice, Inbred BALB C; Mice, Nude; multidisciplinary; Neuropilin; Oligopeptides - therapeutic use; PD-1 protein; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - pathology; Phosphatidylethanolamines - chemistry; Phosphorylation; Phosphotyrosine - metabolism; Polyethylene Glycols - chemistry; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Science; Science (multidisciplinary); Solid tumors; Spheroids; Spheroids, Cellular - metabolism; Stomach Neoplasms - immunology; Stomach Neoplasms - pathology; Stomach Neoplasms - therapy; Subcutaneous Tissue - pathology; Tumors; Tyrosine; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09296-6

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. The therapeutic efficacy of adoptive T cell transfer is limited by their ability to infiltrate solid tumours. Here, the authors show that loading the tumor penetrating cyclic peptide iRGD on the cell surface of T cells enhances their ability to penetrate the tumour, resulting in enhanced efficacy in a mouse model of gastric cancer.