Poor clinical outcomes of intratumoral dendritic cell–specific intercellular adhesion molecule 3–grabbing non-integrin–positive macrophages associated with immune evasion in gastric cancer. (March 2020)

• Record Type: Journal Article
• Authors: Liu, Xin; Cao, Yifan; Li, Ruochen; Gu, Yong; Chen, Yifan; Qi, Yangyang; Lv, Kunpeng; Wang, Jieti; Yu, Kuan; Lin, Chao; Liu, Hao; Zhang, Heng; He, Hongyong; Chen, Lingli; Zhang, Peipei; Shen, Zhenbin; Qin, Jing; Sun, Yihong; Li, He; Huang, Hua; Zhang, Weijuan; Xu, Jiejie
• Is Part Of: European journal of cancer. Volume 128(2020)
• Page Start: 27
• Page End: 37
• Publication Date: 2020-03
• Subjects: Gastric cancer -- Tumour-associated macrophages -- Immune evasion -- Prognosis -- Adjuvant chemotherapy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2020.01.002
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Aim: Tumour-associated macrophages (TAMs) are prominent immune cells infiltrating in solid tumours with phenotypic and functional heterogeneity. However, the clinical significance of heterogeneous subtypes of TAMs in gastric cancer still remains obscure. Here, we aimed to explore the clinical significance of TAMs expressing dendritic cell–specific intercellular adhesion molecule 3–grabbing non-integrin (DC-SIGN) and its relevance with immune contexture in gastric cancer. Methods: We selected 453 formalin-fixed and paraffin-embedded samples and 51 fresh tissue specimens of patients with gastric cancer from Zhongshan Hospital. The association of DC-SIGN + macrophages with clinicopathological parameters, overall survival (OS) and responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) was inspected. Immunohistochemistry (IHC) and flow cytometry (FCM) were applied to characterize immune cells in gastric cancer. Results: We demonstrated that high intratumoral DC-SIGN + macrophages infiltration predicted poor OS and inferior therapeutic responsiveness to fluorouracil-based ACT in patients with gastric cancer. Furthermore, higher infiltration of DC-SIGN + macrophages indicated an increased number of Foxp3 + regulatory T cells (Tregs), CD8 + T cells and a higher ratio of Foxp3 + /CD8 + within the tumour microenvironment (TME). In addition, CD8 + T cells in DC-SIGN + macrophages high subgroup were functionally impaired, showing decreased interferon-γ (IFN-γ), granzyme B (GZMB) and perforin production yet elevated programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression. Conclusions: DC-SIGN + macrophages were associated with immunoinvasive TME and indicated poor prognosis and inferior therapeutic responsiveness to fluorouracil-based ACT. DC-SIGN + macrophages might be an independent prognosticator and a potential immunotherapeutic target for gastric cancer. Graphical abstract: Image 1 Highlights: Dendritic cell–specific intercellular adhesion molecule 3–grabbing non-integrin–positive (DC-SIGN + ) macrophages predict adverse overall survival in gastric cancer (GC). DC-SIGN + macrophages attenuate responsiveness to fluorouracil-based adjuvant chemotherapy in GC. DC-SIGN + macrophages are associated with immune evasion in GC. DC-SIGN + macrophages are associated with exhausted CD8 + T cells in GC. DC-SIGN + macrophages are potential targets for immunotherapy in GC.