Targeted Delivery of CXCL9 and OX40L by Mesenchymal Stem Cells Elicits Potent Antitumor Immunity.

Abstract

Major obstacles in immunotherapies include toxicities associated with systemic administration of therapeutic agents, as well as low tumor lymphocyte infiltration that hampers the efficacies. In this study, we report a mesenchymal stem cell (MSC)-based immunotherapeutic strategy in which MSCs specifically deliver T/natural killer (NK) cell-targeting chemokine CXCL9 and immunostimulatory factor OX40 ligand (OX40L)/tumor necrosis factor superfamily member 4 (TNFSF4) to tumor sites in syngeneic subcutaneous and azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced spontaneous colon cancer mouse models. This approach generated potent local antitumor immunity by increasing the ratios of tumor-infiltrating CD8+ T and NK cells and production of antitumor cytokines and cytolytic proteins in the tumor microenvironment. Moreover, it improved the efficacy of programmed death-1 (PD-1) blockade in a syngeneic mouse model and significantly suppressed the growth of major histocompatibility complex class I (MHC class I)-deficient tumors. Our MSC-based immunotherapeutic strategy simultaneously recruits and activates immune effector cells at the tumor site, thus overcoming the problems with toxicities of systemic therapeutic agents and low lymphocyte infiltration of solid tumors.

• Authors: Pan Yin, Liming Gui, Caihong Wang, Jingjing Yan, Min Liu, Lu Ji, You Wang, Bin Ma, Wei-Qiang Gao
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 28 Issue 12 Pg. 2553-2563 (12 02 2020) ISSN: 1525-0024 [Electronic] United States
• PMID: 32827461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Chemokine CXCL9
• Cxcl9 protein, mouse
• OX40 Ligand
• Tnfsf4 protein, mouse
• Dextran Sulfate
• Azoxymethane

Topics

• Animals
• Azoxymethane (adverse effects)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Chemokine CXCL9 (genetics, metabolism)
• Colonic Neoplasms (chemically induced, immunology, pathology, therapy)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Immunotherapy, Adoptive (methods)
• Killer Cells, Natural (immunology)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Mesenchymal Stem Cell Transplantation (methods)
• Mesenchymal Stem Cells (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• OX40 Ligand (genetics, metabolism)
• Transduction, Genetic
• Transplantation, Isogeneic
• Treatment Outcome
• Tumor Microenvironment (immunology)