Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells
Yuichi Iida, Rintaro Yoshikawa, Akihiko Murata, Hitoshi Kotani, Yasuhiro Kazuki, Mitsuo Oshimura, Yumi Matsuzaki, Mamoru Harada
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)-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. 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-γ + CD8 + T cells, and that combination with anti-PD-L1 antibody therapy can be a powerful anticancer therapy.