Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy to Enhance Cytotoxic T Cell Infiltration and Tumor Control

Zipeng Zhen, Wei Tang, Mengzhe Wang, Shiyi Zhou, Hui Wang, Zhanhong Wu, Zhonglin Hao, Zibo Li, Lin Liu, Jin Xie

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Carcinoma-associated fibroblasts (CAFs) are found in many types of cancer and play an important role in tumor growth and metastasis. Fibroblast-activation protein (FAP), which is overexpressed on the surface of CAFs, has been proposed as a universal tumor targeting antigen. However, recent studies show that FAP is also expressed on multipotent bone marrow stem cells. A systematic anti-FAP therapy may lead to severe side effects and even death. Hence, there is an urgent need of a therapy that can selectively kill CAFs without causing systemic toxicity. Herein we report a nanoparticle-based photoimmunotherapy (nano-PIT) approach that addresses the need. Specifically, we exploit ferritin, a compact nanoparticle protein cage, as a photosensitizer carrier, and we conjugate to the surface of ferritin a FAP-specific single chain variable fragment (scFv). With photoirradiation, the enabled nano-PIT efficiently eliminates CAFs in tumors but causes little damage to healthy tissues due to the localized nature of the treatment. Interestingly, while not directly killing cancer cells, the nano-PIT caused efficient tumor suppression in tumor-bearing immunocompetent mice. Further investigations found that the nano-PIT led to suppressed C-X-C motif chemokine ligand 12 (CXCL12) secretion and extracellular matrix (ECM) deposition, both of which are regulated by CAFs in untreated tumors and mediate T cell exclusion that prevents physical contact between T cells and cancer cells. By selective killing of CAFs, the nano-PIT reversed the effect, leading to significantly enhanced T cell infiltration, followed by efficient tumor suppression. Our study suggests a new and safe CAF-targeted therapy and a novel strategy to modulate tumor microenvironment (TME) for enhanced immunity against cancer.

Original languageEnglish (US)
Pages (from-to)862-869
Number of pages8
JournalNano Letters
Volume17
Issue number2
DOIs
StatePublished - Feb 8 2017

Keywords

  • Photodynamic therapy
  • carcinoma-associated fibroblast
  • cytotoxic T cells
  • fibroblast-activation protein
  • immunotherapy

ASJC Scopus subject areas

  • Bioengineering
  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics
  • Mechanical Engineering

Fingerprint Dive into the research topics of 'Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy to Enhance Cytotoxic T Cell Infiltration and Tumor Control'. Together they form a unique fingerprint.

  • Cite this