Zhang Jing, Xu Xiongfei, Shi Min, Chen Ying, Yu Danghui, Zhao Chenyan, Gu Yan, Yang Biao, Guo Shiwei, Ding Guiling, Jin Gang, Wu Chin-Lee, Zhu Minghua
Department of Pathology, Changhai Hospital, Second Military Medical University , Shanghai, China.
Department of Pathophysiology, Second Military Medical University , Shanghai, China.
Oncoimmunology. 2017 Jan 9;6(2):e1258504. doi: 10.1080/2162402X.2016.1258504. eCollection 2017.
Perineural invasion and immunosuppressive tumor microenvironment are the distinct features of pancreatic ductal adenocarcinoma (PDAC). Heterogeneous myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity, posing obstacles for cancer immunotherapy. Increasing evidences have demonstrated the accumulation of MDSCs in PDAC patients. However, the role of MDSCs in perineural invasion of PDAC and the existence of novel MDSC subsets during PDAC remain unclear. This study found that lymphocytic perineural cuffs were frequently present in chronic pancreatitis (CP) tissues and adjacent non-neoplastic pancreatic tissues (ANPTs), but not in PDAC with perineural invasion. Meanwhile, we found that neutrophil-like MDSCs (nMDSCs), but not monocyte-like MDSCs (mMDSCs), were significantly increased in PBMCs and tumor tissues of PDAC patients. Further observation identified two distinct subsets of nMDSCs, CD13 and CD13 nMDSCs in PDAC patients, which have not been reported previously. Despite a similar morphology, CD13 nMDSCs expressed higher levels of CD11b, CD33, CD16 and arginase 1 but lower levels of CD66b than CD13 nMDSCs. Importantly, CD13 MDSCs, compared with CD13 nMDSCs, more effectively suppressed alloreactive T cell responses via an arginase-1-related mechanism. After tumor resection, the circulating CD13 nMDSCs were decreased markedly. PDAC patients with more CD13 nMDSCs had a shorter overall survival than those with less CD13 nMDSCs. To conclude, we identified two novel MDSC subsets with different characteristics and functions in PDAC, demonstrated the association of the two MDSC subsets with cancer progression, and explored their roles in perineural invasion and immune escape of PDAC.
神经周围浸润和免疫抑制性肿瘤微环境是胰腺导管腺癌（PDAC）的显著特征。异质性骨髓来源的抑制性细胞（MDSCs）是抗肿瘤免疫的强效抑制剂，为癌症免疫治疗带来了障碍。越来越多的证据表明PDAC患者体内存在MDSCs的积累。然而，MDSCs在PDAC神经周围浸润中的作用以及PDAC期间新型MDSC亚群的存在仍不清楚。本研究发现，淋巴细胞性神经周围套袖在慢性胰腺炎（CP）组织和相邻的非肿瘤性胰腺组织（ANPTs）中经常出现，但在伴有神经周围浸润的PDAC中则不存在。同时，我们发现PDAC患者的外周血单个核细胞（PBMCs）和肿瘤组织中，嗜中性粒细胞样MDSCs（nMDSCs）显著增加，而单核细胞样MDSCs（mMDSCs）则没有。进一步观察发现，PDAC患者中存在两个不同的nMDSC亚群，即CD13⁺和CD13⁻ nMDSCs，这是以前未曾报道过的。尽管形态相似，但CD13⁺ nMDSCs比CD13⁻ nMDSCs表达更高水平的CD11b、CD33、CD16和精氨酸酶1，但CD66b水平较低。重要的是，与CD13⁻ nMDSCs相比，CD13⁺ MDSCs通过精氨酸酶-1相关机制更有效地抑制同种异体反应性T细胞反应。肿瘤切除后，循环中的CD13⁺ nMDSCs明显减少。CD13⁺ nMDSCs较多的PDAC患者总生存期比CD13⁺ nMDSCs较少的患者短。总之，我们在PDAC中鉴定出两个具有不同特征和功能的新型MDSC亚群，证明了这两个MDSC亚群与癌症进展的关联，并探讨了它们在PDAC神经周围浸润和免疫逃逸中的作用。
