Intratumoral delivery of CCL25 enhances immunotherapy against triple-negative breast cancer by recruiting CCR9+ T cells.

Abstract

CCR9+ T cells have an increased potential to be activated and therefore may mediate strong antitumor responses. Here, we found, however, that CCL25, the only chemokine for CCR9+ cells, is not expressed in human or murine triple-negative breast cancers (TNBCs), raising a hypothesis that intratumoral delivery of CCL25 may enhance antitumor immunotherapy in TNBCs. We first determined whether this approach can enhance CD47-targeted immunotherapy using a tumor acidity-responsive nanoparticle delivery system (NP-siCD47/CCL25) to sequentially release CCL25 protein and CD47 small interfering RNA in tumor. NP-siCD47/CCL25 significantly increased infiltration of CCR9+CD8+ T cells and down-regulated CD47 expression in tumor, resulting in inhibition of tumor growth and metastasis through a T cell-dependent immunity. Furthermore, the antitumor effect of NP-siCD47/CCL25 was synergistically enhanced when used in combination with programmed cell death protein-1/programmed death ligand-1 blockades. This study offers a strategy to enhance immunotherapy by promoting CCR9+CD8+ T cell tumor infiltration.

• Authors: Hongmei Chen, Xiuxiu Cong, Chenxi Wu, Xuan Wu, Jialiang Wang, Kuirong Mao, Jie Li, Ge Zhu, Feiqi Liu, Xiandi Meng, Jia Song, Xu Sun, Xin Wang, Shuhan Liu, Shi Zhang, Xianzhu Yang, Yanqiu Song, Yong-Guang Yang, Tianmeng Sun
• Journal: Science advances (Sci Adv) Vol. 6 Issue 5 Pg. eaax4690 (01 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 32064335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Chemical References

• CC chemokine receptor 9
• CCL25 protein, human
• CD47 Antigen
• Chemokines, CC
• RNA, Small Interfering
• Receptors, CCR

Topics

• Animals
• CD47 Antigen (antagonists & inhibitors, genetics, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Chemokines, CC (antagonists & inhibitors, genetics, pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunotherapy
• Mice
• Nanoparticles (chemistry)
• Neoplasm Metastasis
• RNA, Small Interfering (genetics, pharmacology)
• Receptors, CCR (genetics, immunology)
• T-Lymphocytes (drug effects, immunology)
• Triple Negative Breast Neoplasms (drug therapy, genetics, immunology, pathology)