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

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.