Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells

• Published in: Journal for immunotherapy of cancer Vol. 8; no. 2; p. e000582
• Main Authors: Iida, Yuichi, Yoshikawa, Rintaro, Murata, Akihiko, Kotani, Hitoshi, Kazuki, Yasuhiro, Oshimura, Mitsuo, Matsuzaki, Yumi, Harada, Mamoru
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.07.2020; BMJ Publishing Group
• Series: Original research
• Subjects: Antibodies; Antigens; Bone marrow; Cancer; Cell death; Chemokines; Cloning; Experiments; Fibroblasts; Immune Cell Therapies and Immune Cell Engineering; Immunotherapy; Laboratories; Ligands; Lymphocytes; Tumors; United States > US; Japan; programmed cell death 1 receptor; cell engineering; dendritic cells; tumor microenvironment; immunotherapy
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2020-000582

Mesenchymal stem/stromal cells (MSC) accumulate and reside in tumor sites. 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. 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)-γ 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. 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-γ CD8 T cells, and that combination with anti-PD-L1 antibody therapy can be a powerful anticancer therapy.