Maruyama Akira, Shime Hiroaki, Takeda Yohei, Azuma Masahiro, Matsumoto Misako, Seya Tsukasa
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Biochem Biophys Res Commun. 2015 Feb 13;457(3):445-50. doi: 10.1016/j.bbrc.2015.01.011. Epub 2015 Jan 13.
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exhibit potent immunosuppressive activity. They are increased in tumor-bearing hosts and contribute to tumor development. Toll-like receptors (TLRs) on MDSCs may modulate the tumor-supporting properties of MDSCs through pattern-recognition. Pam2 lipopeptides represented by Pam2CSK4 serve as a TLR2 agonist to exert anti-tumor function by dendritic cell (DC)-priming that leads to NK cell activation and cytotoxic T cell proliferation. On the other hand, TLR2 enhances tumor cell progression/invasion by activating tumor-infiltrating macrophages. How MDSCs respond to TLR2 agonists has not yet been determined. In this study, we found intravenous administration of Pam2CSK4 systemically up-regulated the frequency of MDSCs in EG7 tumor-bearing mice. The frequency of tumor-infiltrating MDSCs was accordingly increased in response to Pam2CSK4. MDSCs were not increased by Pam2CSK4 stimuli in TLR2 knockout (KO) mice. Adoptive transfer experiments using CFSE-labeled MDSCs revealed that the TLR2-positive MDSCs survived long in tumor-bearing mice in response to Pam2CSK4 treatment. Since the increased MDSC population sustained immune-suppressive properties, our study suggests that Pam2CSK4-triggered TLR2 activation enhances the MDSC potential and suppress antitumor immune response in tumor microenvironment.
髓系来源的抑制性细胞（MDSCs）是具有强大免疫抑制活性的未成熟髓系细胞。它们在荷瘤宿主中数量增加，并促进肿瘤发展。MDSCs上的Toll样受体（TLRs）可能通过模式识别来调节MDSCs的肿瘤支持特性。以Pam2CSK4为代表的Pam2脂肽作为TLR2激动剂，通过树突状细胞（DC）启动发挥抗肿瘤功能，从而导致自然杀伤细胞（NK细胞）活化和细胞毒性T细胞增殖。另一方面，TLR2通过激活肿瘤浸润巨噬细胞来促进肿瘤细胞的进展/侵袭。MDSCs对TLR2激动剂的反应尚未确定。在本研究中，我们发现静脉注射Pam2CSK4可使荷EG7肿瘤小鼠体内的MDSCs频率系统性上调。相应地，肿瘤浸润MDSCs的频率因Pam2CSK4而增加。在TLR2基因敲除（KO）小鼠中，Pam2CSK4刺激不会增加MDSCs。使用CFSE标记的MDSCs进行的过继转移实验表明，TLR2阳性的MDSCs在接受Pam2CSK4治疗的荷瘤小鼠中存活时间较长。由于增加的MDSC群体维持了免疫抑制特性，我们的研究表明，Pam2CSK4触发的TLR2激活增强了MDSC的潜能，并抑制了肿瘤微环境中的抗肿瘤免疫反应。
