Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
Institute of Pathology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-001813.
Plasmacytoid dendritic cells (pDCs) play a key role in the induction and maintenance of antitumor immunity. Conversely, they can act as tolerogenic DCs by inhibiting tumor-directed immune responses. Therefore, pDCs may profoundly influence tumor progression. To gain novel insights into the role of pDCs in colon cancer, we investigated the frequency and clinical relevance of pDCs in primary tumor tissues from patients with colon cancer with different clinicopathological characteristics.
Immunohistochemical stainings were performed to explore the frequency of tumor-infiltrating BDCA-2 pDCs in patients with colon cancer. Statistical analyses were conducted to determine an association between the pDC density and clinicopathological characteristics of the patients. Furthermore, we used multiplex immunofluorescence stainings to evaluate the localization and phenotype of pDCs in stroma and tertiary lymphoid structures (TLS) of colon cancer tissues.
An increased density of infiltrating pDCs was associated with lower Union for International Cancer Control (UICC) stages. Furthermore, a higher pDC frequency was significantly correlated with increased progression-free and overall survival of patients with colon cancer. Moreover, a lower number of coloncancer-infiltrating pDCs was significantly and independently linked to worse prognosis. In addition, we found that a proportion of pDCs shows a nuclear expression of the transcription factor interferon regulatory factor 7 (IRF7), which is characteristic for an activated phenotype. In various tumor stroma regions, IRF7 pDCs were located in the neighborhood of granzyme B-expressing CD8 T cells. Moreover, pDCs were identified as a novel component of the T cell zone of colon cancer-associated TLS, which are major regulators of adaptive antitumor immunity. A proportion of TLS-associated pDCs displayed a nuclear IRF7 expression and was preferentially located close to CD4 T cells.
These results indicate that higher densities of tumor-infiltrating pDCs are associated with prolonged survival of patients with colon cancer. Moreover, colon cancer-infiltrating pDCs may represent a novel prognostic factor. The colocalization of activated pDCs and T cells in tumor stroma and within TLS may contribute to the correlation between higher pDC densities and better prognosis. In addition, our findings may have implications for the design of novel immunotherapeutic strategies that are based on targeting colon cancer-infiltrating pDCs.
浆细胞样树突状细胞（pDCs）在诱导和维持抗肿瘤免疫中发挥关键作用。相反，它们可以通过抑制肿瘤定向免疫反应而充当耐受性 DCs。因此，pDCs 可能会深刻影响肿瘤的进展。为了深入了解 pDCs 在结肠癌中的作用，我们研究了具有不同临床病理特征的结肠癌患者原发肿瘤组织中 pDCs 的频率和临床相关性。
通过免疫组织化学染色来探索结肠癌患者肿瘤浸润性 BDCA-2 pDCs 的频率。进行统计学分析以确定 pDC 密度与患者临床病理特征之间的关联。此外，我们使用多重免疫荧光染色来评估结肠癌组织中基质和三级淋巴结构（TLS）中 pDCs 的定位和表型。
浸润性 pDCs 密度的增加与较低的国际癌症控制联盟（UICC）分期相关。此外，pDC 频率的增加与结肠癌患者无进展生存期和总生存期的延长显著相关。此外，结肠癌浸润性 pDCs 的数量减少与预后不良显著相关。此外，我们发现一部分 pDCs 表现出转录因子干扰素调节因子 7（IRF7）的核表达，这是其激活表型的特征。在各种肿瘤基质区域，IRF7 pDCs 位于表达颗粒酶 B 的 CD8 T 细胞附近。此外，pDCs 被鉴定为结肠癌相关 TLS 的 T 细胞区的一个新成分，TLS 是适应性抗肿瘤免疫的主要调节因子。一部分 TLS 相关 pDCs 表现出核 IRF7 表达，并优先位于 CD4 T 细胞附近。
这些结果表明，肿瘤浸润性 pDCs 的密度较高与结肠癌患者的生存时间延长相关。此外，结肠癌浸润性 pDCs 可能是一个新的预后因素。在肿瘤基质和 TLS 中激活的 pDCs 与 T 细胞的共定位可能导致更高的 pDC 密度与更好的预后之间的相关性。此外，我们的研究结果可能对基于靶向结肠癌浸润性 pDCs 的新型免疫治疗策略的设计具有启示意义。
