De Silva Nadeeka H, Akazawa Takashi, Wijewardana Viskam, Inoue Norimitsu, Oyamada Maremichi, Ohta Atsuko, Tachibana Yuki, Wijesekera Daluthgamage Patsy H, Kuwamura Mitsuru, Nishizawa Yasuko, Itoh Kazuyuki, Izawa Takeshi, Hatoya Shingo, Hasegawa Tetsuya, Yamate Jyoji, Inaba Toshio, Sugiura Kikuya
Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan.
Department of Tumor Immunology, Osaka International Cancer Institute, Osaka, Japan.
PLoS One. 2017 Nov 30;12(11):e0188738. doi: 10.1371/journal.pone.0188738. eCollection 2017.
Although dendritic cell (DC)-based immunotherapy shows little toxicity, improvements should be necessary to obtain satisfactory clinical outcome. Using interferon-gamma injection along with DCs, we previously obtained significant clinical responses against small or early stage malignant tumors in dogs. However, improvement was necessary to be effective to largely developed or metastatic tumors. To obtain effective methods applicable to those tumors, we herein used a DC-targeting Toll-like receptor ligand, h11c, and examined the therapeutic effects in murine subcutaneous and visceral tumor models and also in the clinical treatment of canine cancers. In murine experiments, most and significant inhibition of tumor growth and extended survival was observed in the group treated with the combination of h11c-activated DCs in combination with interferon-gamma and a cyclooxygenase2 inhibitor. Both monocytic and granulocytic myeloid-derived suppressor cells were significantly reduced by the combined treatment. Following the successful results in mice, the combined treatment was examined against canine cancers, which spontaneously generated like as those in human. The combined treatment elicited significant clinical responses against a nonepithelial malignant tumor and a malignant fibrous histiocytoma. The treatment was also successful against a bone-metastasis of squamous cell carcinoma. In the successful cases, the marked increase of tumor-responding T cells and decrease of myeloid-derived suppressor cells and regulatory T cells was observed in their peripheral blood. Although the combined treatment permitted the growth of lung cancer of renal carcinoma-metastasis, the marked elevated and long-term maintaining of the tumor-responding T cells was observed in the patient dog. Overall, the combined treatment gave rise to emphatic amelioration in DC-based cancer therapy.
尽管基于树突状细胞（DC）的免疫疗法毒性很小，但仍需改进以获得令人满意的临床效果。我们之前通过联合注射干扰素-γ和DC，在犬类身上针对小型或早期恶性肿瘤取得了显著的临床反应。然而，对于大型或转移性肿瘤，仍需改进治疗方法以提高疗效。为了找到适用于这些肿瘤的有效方法，我们在此使用了一种靶向DC的Toll样受体配体h11c，并在小鼠皮下和内脏肿瘤模型以及犬类癌症的临床治疗中研究了其治疗效果。在小鼠实验中，用h11c激活的DC联合干扰素-γ和环氧化酶2抑制剂治疗的组中，观察到肿瘤生长受到最显著的抑制，生存期延长。联合治疗显著减少了单核细胞和粒细胞来源的抑制性细胞。在小鼠实验取得成功后，我们对犬类癌症进行了联合治疗研究，犬类癌症与人类癌症一样会自发产生。联合治疗对非上皮性恶性肿瘤和恶性纤维组织细胞瘤引发了显著的临床反应。该治疗方法对鳞状细胞癌的骨转移也取得了成功。在成功的病例中，其外周血中肿瘤反应性T细胞显著增加，髓源性抑制细胞和调节性T细胞减少。尽管联合治疗未能抑制肾癌转移的肺癌生长，但在患病犬中观察到肿瘤反应性T细胞显著升高并长期维持。总体而言，联合治疗在基于DC的癌症治疗中带来了显著改善。
