Abstract
Macrophages constitute a major component of tumor-infiltrating immune cells. M2 macrophages have been reported to promote tumor progression through promoting tumor angiogenesis and metastasis and regulating T-cell function. Here, we identified a protumorigenic subset of macrophages that constitutively expressed programmed cell death 1 (PD1) and accumulated in advanced-stage gastric cancer (GC). These PD1+ tumor-associated macrophages (TAMs) exhibited an M2-like surface profile, with a significant increase in the expression of CD206, IL-10, and CCL1, and a clear decrease in the expression of MHC class II, CD64, and IL-12 and the ability to phagocytose ovalbumin. Moreover, PD1+ TAMs can suppress CD8+ T-cell function and this immunosuppressive activity can effectively be enhanced upon triggering PD1 signal. GC-derived exosomes effectively educated monocytes to differentiate into PD1+ TAMs with M2 phenotypic and functional characteristics. Together, our results are the first to show that GC-derived exosomes can effectively induce PD1+ TAM generation, and these cells can produce a large number of IL-10, impair CD8+ T-cell function, and thereby create conditions that promote GC progression. Thus, methods in which immunotherapy is combined with targeting PD1+ TAMs and tumor-derived exosomes should be used to restore immune function in GC patients.
Highlights
Gastric cancer (GC), which is the fourth most common malignant tumor, is the third leading cause of cancerrelated death in the world[1]
The results showed that programmed cell death 1 (PD1)+ macrophages were accumulated at GC tissue (Fig. 1d, e)
We assessed the clinical relevance of intratumorous PD1+ macrophages in GC patients (Tables 1 and 2), and found that the proportions of PD1+ macrophages determined by flow cytometry were significantly associated with disease progression in 26 GC patients (Fig. 1f, Table 1), and that the number of PD1+ macrophages determined by immunofluorescence staining was significantly associated with disease progression in 15 GC patients (Fig. 1g, Table 2)
Summary
Gastric cancer (GC), which is the fourth most common malignant tumor, is the third leading cause of cancerrelated death in the world[1]. Helicobacter pylori (HP) infection is the main risk factor for the progression of chronic gastritis[2] which is mainly composed of extracellular matrix, activated cancer-associated fibroblasts, and immune cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Treg), and regulatory B cells (Breg), which accelerates GC progression. Macrophages (Mφs) are a major component of tumorinfiltrating immune cells[3,4], and associate with poor prognosis in tumor[5]. Recent studies have confirmed that TAMs can accelerate tumor angiogenesis[6], metastasis[7], and influence the T-cell activation and differentiation via the cytokine secretion[8,9].
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