Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients

Abstract

CD47 is known to be involved in phagocyte-mediated tumor clearance; however, its expression, clinical significance, and regulatory mechanism in hepatocellular carcinoma (HCC) remain poorly understood. In the present study, we found that upregulation of CD47 expression on tumor cells was correlated with poor overall survival and recurrence-free survival in patients with HCC. Abundance of macrophages (Mφs) infiltration was found in CD47 + tumor tissues. Mechanistic studies revealed that IL-6 derived from tumorinfiltrating Mφs could upregulate CD47 expression on hepatoma cells through activation of the STAT3 pathway. Neutralization of CD47 or disruption of the IL-6-STAT3 axis reduced the ability of tumor cells to escape phagocytosis. Moreover, CD47 blockade could enhance Mφ-mediated phagocytosis in the presence of chemotherapeutic drugs, and HCC patients with lower CD47 expression were more likely to benefit from adjuvant transcatheter arterial chemoembolization (TACE) treatment. These findings revealed that Mφderived IL-6 was responsible for CD47 expression on hepatoma cells, which might be served as a potential prognostic marker and a predictor for patients who might benefit from adjuvant TACE treatment.

Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes

“…In this study, we also identified that the elevated CD47 expression is correlated with poor survival in HCCs, which is consistent with previous observations [25,[47][48][49][50][51]. In 2015, William C Chapman et al have shown that blocking CD47 with specific antibodies has therapeutic efficacy in human HCC [52].…”

“…To elucidate the clinical significance of the upregulated immune checkpoints, we analyzed the relationship between these genes and overall survival (OS) of HCC patients. The results show that only two genes are significantly associated with poor OS: CD276 (B7-H3) (P = 0.014, Figure 2A) and CD47 (P = 0.039, Figure 2B), consistent with previous reports [20][21][22][23][24][25]. All the others do not have a statistically significant relationship with survival ( Supplementary Figure 1).…”

<p>CD47 Overexpression Is Associated with Epstein–Barr Virus Infection and Poor Prognosis in Patients with Nasopharyngeal Carcinoma</p>

“…30 Interleukin (IL)-6 has been demonstrated to upregulate CD47 expression on hepatoma cells by activating the signal transducer and activator of transcription 3 (STAT3) pathway. 31 In addition, LMP1 upregulated c-myc via IL-6 induction followed by Jak3/STAT3 activation 32 and it also upregulated PD-L1 via the STAT3, activator protein (AP)-1, and nuclear factor (NF)kappa B pathways. 19 Therefore, we infer that LMP1 may upregulate CD47 expression via the c-myc/IL-6/STAT3 pathway.…”

Surface-exposed and soluble calreticulin: conflicting biomarkers for cancer prognosis

“…Thus the overabundance of CD47 may potentially play an important role in tumor cell evasion. [22][23][24][25][26][27] Soluble CALR can be passively released or actively secreted from cells, as this occurs in the context of massive cell death upon anticancer chemotherapy. Moreover, CALR can be secreted by macrophages stimulated by toll-like receptor (TLR) agonists and then contributes to the recognition and phagocytosis of adjacent tumor cells.…”