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

Xin Liu; Yifan Cao; Ruochen Li; Yong Gu; Yifan Chen; Yangyang Qi; Kunpeng Lv; Jieti Wang; Kuan Yu; Chao Lin; Hao Liu; Heng Zhang; Hongyong He; Lingli Chen; Peipei Zhang; Zhenbin Shen; Jing Qin; Yihong Sun; He Li; Hua Huang; Weijuan Zhang; Jiejie Xu

doi:10.1016/j.ejca.2020.01.002

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

Eur J Cancer. 2020 Mar:128:27-37. doi: 10.1016/j.ejca.2020.01.002. Epub 2020 Mar 5.

Authors

Xin Liu¹, Yifan Cao², Ruochen Li², Yong Gu¹, Yifan Chen³, Yangyang Qi³, Kunpeng Lv¹, Jieti Wang⁴, Kuan Yu², Chao Lin², Hao Liu², Heng Zhang², Hongyong He², Lingli Chen⁵, Peipei Zhang⁶, Zhenbin Shen², Jing Qin², Yihong Sun², He Li⁷, Hua Huang⁸, Weijuan Zhang⁹, Jiejie Xu¹⁰

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
² Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁴ Department of Gastric Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China.
⁵ Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: li.he@zs-hospital.sh.cn.
⁸ Department of Gastric Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China. Electronic address: huahuang@fudan.edu.cn.
⁹ Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: weijuanzhang@fudan.edu.cn.
¹⁰ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: jjxufdu@fudan.edu.cn.

PMID: 32109848
DOI: 10.1016/j.ejca.2020.01.002

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.

Keywords: Adjuvant chemotherapy; Gastric cancer; Immune evasion; Prognosis; Tumour-associated macrophages.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Cell Adhesion Molecules / metabolism*
Chemotherapy, Adjuvant / methods
Drug Resistance, Neoplasm / immunology
Female
Fluorouracil / pharmacology
Fluorouracil / therapeutic use
Follow-Up Studies
Gastrectomy
Humans
Kaplan-Meier Estimate
Lectins, C-Type / metabolism*
Macrophages / immunology*
Macrophages / metabolism
Male
Middle Aged
Receptors, Cell Surface / metabolism*
Stomach / cytology
Stomach / immunology
Stomach / pathology
Stomach / surgery
Stomach Neoplasms / immunology*
Stomach Neoplasms / mortality
Stomach Neoplasms / pathology
Stomach Neoplasms / therapy
Treatment Outcome
Tumor Escape*

Substances

Cell Adhesion Molecules
DC-specific ICAM-3 grabbing nonintegrin
Lectins, C-Type
Receptors, Cell Surface
Fluorouracil