Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells
Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells
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DOI：
10.1136/jitc-2020-000582
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Harada, Mamoru
中科院分区：
文献类型：
--
作者：
Iida, Yuichi;Yoshikawa, Rintaro;Harada, Mamoru
背景间充质干细胞/基质细胞（MSC）积聚并驻留在肿瘤部位。方法利用小鼠骨髓间充质干细胞（immortalized murine MSC，iMSC）的趋化因子（chemokine，C-C motif）配体19（chemokine，C-C motif）配体19，iMSC/CCL 19，能吸引树突状细胞（dendritic cell，DC）和T淋巴细胞。此后，使用同基因CT 26结肠癌细胞系检查iMSC/CCL 19的治疗功效。结果与表达CCL 19的永生化成纤维细胞（iFib/CCL 19）相比，iMSC/CCL 19共注射可显著抑制CT 26细胞的体内生长。当在携带CT 26的裸鼠中注射时，未观察到这种抗癌作用。共注射的iMSC/CCL 19在肿瘤部位的存活时间长于iFib/CCL 19。在治疗模型中，局部注射iMSC/CCL 19抑制了肿瘤生长，并且当用iMSC/CCL 19治疗时观察到肿瘤部位中IFN（干扰素）-γ（+）CD 8（+）T细胞和CCR 7（+）DC浸润增加，但用iMSC治疗则没有。这种抗肿瘤作用完全被CD 4（+）细胞的耗竭所抵消，部分被CD 8（+）细胞的耗竭所抵消。此外，局部注射iMSC/CCL 19诱导的抗肿瘤作用通过使用抗程序性死亡（PD）-配体1（PD-L1）抗体的额外治疗而增强，但不使用抗PD-1抗体。这种联合疗法治愈了携带CT 26的小鼠中的大多数肿瘤。结论iMSC/CCL 19局部治疗可通过有效募集CCR 7（+）DC进入肿瘤部位并增加IFN-γ（+）CD 8（+）T细胞来抑制肿瘤生长，联合抗PD-L1抗体治疗可成为一种有效的抗肿瘤治疗方法。
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.