Original ResearchPoor clinical outcomes of intratumoral dendritic cell–specific intercellular adhesion molecule 3–grabbing non-integrin–positive macrophages associated with immune evasion in gastric cancer
Graphical abstract
Introduction
Gastric cancer is one of the leading causes of cancer mortality in the world [1], especially in China, which accounts for more than one-third of the worldwide gastric cancer burden [2]. Radical gastrectomy is the most effective treatment [3], and fluorouracil-based adjuvant chemotherapy (ACT) is a common first-line adjuvant therapy for patients with advanced gastric cancer [4,5]. However, only moderate survival benefit was achieved owing to chemoresistance [6,7]. Recently, immunotherapy aimed at boosting anti-tumour immunity by targeting the tumour microenvironment (TME) has provided a new option for adjuvant therapy [8,9]. Immune checkpoint inhibitors such as monoclonal anti-programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) antibodies have been applied to patients with advanced gastric cancer [10,11]. Unfortunately, most patients with gastric cancer do not respond to PD-1/PD-L1 blockade because of the high heterogeneity of immune evasion mechanisms [12,13]. Thus, identification of novel therapeutic targets for reinvigorating anti-tumour immunity is essential for therapeutic resistant patients.
The specific composition, density, and functional status of immune cells infiltration in the TME, which termed the immune contexture, can generate information related to clinical outcomes and therapeutic resistance [14]. Tumour-associated macrophages (TAMs) comprise the majority of tumour-infiltrating immune cells capable of regulating immune responses [15]. Generally, TAMs are considered to polarize into an anti-tumour M1 or a pro-tumour M2 subset [16]. Our previous study has demonstrated that M2 polarized TAMs determine poor prognosis in gastric cancer [17]. However, although these two forms of polarization are attractive, emerging evidence is indicating that TAMs are actually an aggregation of M1 and M2 polarized subtype phenotypes, suggesting such a simple characterization of TAMs is much too limited [15]. In fact, TAMs show significant heterogeneity with various biological functions in tumour progression. Recent studies have proven that targeting phenotypically or functionally specific macrophage subsets can reinvigorate anti-tumour immunity in liver and gastrointestinal cancer [18,19]. Given the wide range of macrophages infiltrated in the TME, targeting specific macrophage subsets to reverse immune evasion within gastric cancer is consequently promising and requires further investigation.
C-type lectin receptors (CLRs) are considered to play an important role in the immunomodulatory ability through the interaction with glycosylated ligands [20,21]. Dendritic cell–specific intercellular adhesion molecule 3–grabbing non-integrin (DC-SIGN, encoded by CD209) is one of the most widely studied CLRs which are mainly expressed on dendritic cells (DCs) and certain macrophages [22]. Although the role of DC-SIGN expression on DCs in pathogen recognition and internalization, DCs migration and adhesion, and T cells differentiation has been widely reported [[23], [24], [25]], its function on macrophages has mostly been overlooked. Recent studies have revealed that DC-SIGN+ macrophages can facilitate immune evasion in lung and breast cancer [26,27]. However, no study has inspected the clinical significance of DC-SIGN+ macrophages and their functional relevance on immune evasion in gastric cancer.
In this study, we found that DC-SIGN+ macrophages could predict poor overall survival (OS) and inferior therapeutic responsiveness to ACT in gastric cancer. Furthermore, DC-SIGN+ macrophages yielded immunoevasive TME with dysfunctional CD8+ T cells. Especially, the DC-SIGN+ macrophage–associated dysfunctional CD8+ T cells could result in poor prognosis in patients with gastric cancer. Regarding the importance and originality of this research, it supported the rational for DC-SIGN+ macrophages mediation effect on immune evasion by studying a large cohort of patients and gastric cancer specimens. These results suggested the clinical significance of DC-SIGN+ macrophages in gastric cancer and indicated DC-SIGN+ macrophages might be a potential immunotherapeutic target for gastric cancer.
Section snippets
Patient cohorts and specimens
This study recruited 496 patients with gastric cancer who underwent radical gastrectomy between August 2007 and December 2008 in Zhongshan Hospital, Fudan University (Shanghai, China) [28]. Forty-three patients were excluded for clinical data missing, metastatic diseases and dot loss. Finally, 453 patients were randomly divided into two independent cohorts, discovery set (n = 200) and validation set (n = 253). Patients’ clinicopathological characteristics were displayed (Table 1). The clinical
DC-SIGN+ macrophages are enriched in intratumoral gastric cancer tissues
We first tested whether CD68+ macrophages expressed DC-SIGN in gastric cancer. Immunofluorescence (IF) staining for CD68 and DC-SIGN revealed that a portion of CD68+ macrophages expressed DC-SIGN (Fig. 1A), suggesting that DC-SIGN+ macrophages were a subset of CD68+ macrophages. Comparing intratumoral and peritumoral DC-SIGN+ macrophages in 453 gastric tissues, we found that DC-SIGN+ macrophages were more abundant in intratumoral tissues (Fig. 1B). Gating strategy used for selection of DC-SIGN+
Discussion
Here, we identified that DC-SIGN+ macrophages were highly infiltrated in a large proportion of patients with gastric cancer. To our knowledge, our study was the first to reveal the relevance of DC-SIGN+ macrophages to poor OS and inferior responsiveness to fluorouracil-based ACT in gastric cancer. Consequently, it was assumed that DC-SIGN+ macrophages could be a potential prognostic and predictive marker for gastric cancer.
The specific immune contexture in the TME can convey potent information
Conclusions
Conclusively, DC-SIGN+ macrophages were found to identify immunoevasive subtype gastric cancer with poor prognosis and suboptimum for ACT, and emphasized a previously unknown role of DC-SIGN+ macrophages in CD8+ T cell dysfunction, with decreased effector molecules IFN-γ, GZMB and perforin production yet enhanced PD-1 and CTLA-4 expression. This study highlighted the importance of DC-SIGN+ macrophages in patient stratification and also offered possibilities to improve the therapeutic strategy
Funding
This study was funded by grants from National Natural Science Foundation of China (81671628, 81672324, 31770851, 81871306, 81871926, 81871930, 81902402, 81902901, 81972219), Shanghai Municipal Natural Science Foundation (18ZR1432900), and Shanghai Sailing Program (17YF1402200, 18YF1404600, 19YF1407500). All these study sponsors have no roles in the study design, in the collection, analysis and interpretation of data.
Author contributions
X.L., Y.F.C., R.C.L. and Y.G. contributed for acquisition of data, analysis and interpretation of data, as well as statistical analysis and drafting of the manuscript; Y.F.C., Y.Y.Q., K.P.L., J.T.W., K.Y., C.L., H.L., H.Z., H.Y.H., L.L.C., P.P.Z., Z.B.S., J.Q. and Y.H.S. contributed for technical and material support; H.L., H.H., W.J.Z. and J.J.X. for study concept and design, analysis and interpretation of data, drafting of the manuscript and also obtained funding and study supervision. All
Conflict of interest statement
The authors declare no conflict of interest.
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These authors contributed equally to this work.