Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells
Open Access
- 1 January 2020
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 8 (2), e000582
- https://doi.org/10.1136/jitc-2020-000582
Abstract
Background Mesenchymal stem/stromal cells (MSC) accumulate and reside in tumor sites. Methods Taking advantage of this feature in anticancer therapy, immortalized murine MSC (iMSC) were genetically altered to produce chemokine (C-C motif) ligand 19 (iMSC/CCL19), which attracts dendritic cells (DC) and T lymphocytes. Thereafter, iMSC/CCL19 were examined for their therapeutic efficacy using a syngeneic CT26 colon carcinoma cell line. Results Co-injection of iMSC/CCL19 into mice significantly suppressed the in vivo growth of CT26 cells compared with that of CCL19-expressing immortalized fibroblasts (iFib/CCL19). This anticancer effect was not observed when injected in CT26-bearing nude mice. Co-injected iMSC/CCL19 survived longer than iFib/CCL19 in the tumor sites. In a therapeutic model, local injection of iMSC/CCL19 suppressed the tumor growth, and increased IFN (interferon)-gamma(+)CD8(+)T cells and CCR7(+)DC infiltration in tumor site was observed when treated with iMSC/CCL19, but not with iMSC. This antitumor effect was completely negated by depletion of CD4(+)cells and partially negated by depletion of CD8(+)cells. Furthermore, the antitumor effects induced by local injection of iMSC/CCL19 were augmented by additional therapy with anti-programmed death (PD)-ligand 1 (PD-L1) antibody, but not with anti-PD-1 antibody. This combination therapy cured most of the tumors in CT26-bearing mice. Conclusion These results suggest that local therapy with iMSC/CCL19 can suppress tumor growth via effective recruitment of CCR7(+)DC into tumor sites and increase IFN-gamma(+)CD8(+)T cells, and that combination with anti-PD-L1 antibody therapy can be a powerful anticancer therapy.Funding Information
- Japan Society for the Promotion of Science (19K16713)
This publication has 43 references indexed in Scilit:
- Use of Mesenchymal Stem Cells (MSC) in Chronic Inflammatory Fistulizing and Fibrotic Diseases: a Comprehensive ReviewClinical Reviews in Allergy & Immunology, 2013
- Human Artificial Chromosome with a Conditional Centromere for Gene Delivery and Gene ExpressionDNA Research, 2010
- Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor ModelCancer Microenvironment, 2010
- Activated Local Immunity by CC Chemokine Ligand 19-Transduced Embryonic Endothelial Progenitor Cells Suppresses Metastasis of Murine Ovarian CancerThe International Journal of Cell Cloning, 2009
- Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrowThe Journal of Experimental Medicine, 2009
- Cyclophosphamide Augments Antitumor Immunity: Studies in an Autochthonous Prostate Cancer ModelCancer Research, 2009
- Concentration-dependent inhibition of angiogenesis by mesenchymal stem cellsBlood, 2009
- Mesenchymal stem cells within tumour stroma promote breast cancer metastasisNature, 2007
- CCL19-IgG Prevents Allograft Rejection by Impairment of Immune Cell TraffickingJournal of the American Society of Nephrology, 2006
- CD4+CD3− Accessory Cells Costimulate Primed CD4 T Cells through OX40 and CD30 at Sites Where T Cells Collaborate with B CellsImmunity, 2003