Clinical significance of signal regulatory protein alpha (SIRPα) expression in esophageal squamous cell carcinoma

Abstract

Signal regulatory protein alpha (SIRPα) is a type I transmembrane protein that inhibits macrophage phagocytosis of tumor cells upon interaction with CD47, and the CD47‐SIRPα pathway acts as an immune checkpoint factor in cancers. This study aims to clarify the clinical significance of SIRPα expression in esophageal squamous cell carcinoma (ESCC). First, we assessed SIRPα expression using RNA sequencing data of 95 ESCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical analytic data from our cohort of 131 patients with ESCC. Next, we investigated the correlation of SIRPα expression with clinicopathological factors, patient survival, infiltration of tumor immune cells, and expression of programmed cell death‐ligand 1 (PD‐L1). Overall survival was significantly poorer with high SIRPα expression than with low expression in both TCGA and our patient cohort (P < .001 and P = .027, respectively). High SIRPα expression was associated with greater depth of tumor invasion (P = .0017). Expression of SIRPα was also significantly correlated with the tumor infiltration of M1 macrophages, M2 macrophages, CD8+ T cells, and PD‐L1 expression (P < .001, P < .001, P = .03, and P < .001, respectively). Moreover, patients with SIRPα/PD‐L1 coexpression tended to have a worse prognosis than patients with expression of either protein alone or neither. Taken together, SIRPα indicates poor prognosis in ESCC, possibly through inhibiting macrophage phagocytosis of tumor cells and inducing suppression of antitumor immunity. Signal regulatory protein alpha should be considered as a potential therapeutic target in ESCC, especially if combined with PD‐1‐PD‐L1 blockade.

High SIRPA Expression Predicts Poor Prognosis and Correlates with Immune Infiltrates in Patients with Esophageal Carcinoma

“…A study conducted by Kaur et al showed that breast cancer cells prevented phagocytosis by macrophages through inducing SIRPA inhibitory signaling and overexpressing CD47 protein [ 10 ]. In Koga et al's cohort, SIRP α protein was overexpressed in esophageal squamous cell carcinoma patients and predicted poor survival [ 11 ].…”

A New Serum Macrophage Checkpoint Biomarker for Innate Immunotherapy: Soluble Signal-Regulatory Protein Alpha (sSIRPα)

“…Firstly, high pre-treatment levels of sSIRPα could potentially signal a poor prognosis reflecting sSIRPα constitutively released by high numbers of TAMs. This is supported by SIRPα being constitutively released by MDMs and by recent evidence linking high SIRPα expression to poor survival in sev-eral tumors [11,[21][22][23][24]. Secondly, a rise in sSIRPα levels after initiation of immunotherapy may reflect the level of immune activation achieved, and thus predict the successfulness of the treatment.…”

“…In this work, we show that SIRPα is present as a stable soluble protein in human blood which we denote sSIRPα. A soluble form of SIRPα has previously been detected in vitro [ 11 , 13 , 14 ], but to our knowledge, this is the first time sSIRPα has been detected in the human circulation.…”

“…SIRPα is normally expressed on neural tissue and on myelomonocytic cells, including monocytes, macrophages, granulocytes, dendritic cells and their precursors [ 4 , 7 , 8 , 9 , 10 ]. SIRPα is also expressed on TAMs, and recent evidence links high SIRPα expression to poor survival in patients with esophageal squamous cell carcinoma [ 11 ]. Thus, SIRPα is both a potential therapeutic target, and a potential biomarker in cancer.…”

Expression of CD47 and SIRPα Macrophage Immune-Checkpoint Pathway in Non-Small-Cell Lung Cancer

“…Contradictory results have been reported in lymphomas [ 14 , 15 ]. A recent study in esophageal cancer showed that SIRPα was directly linked with invasive disease and poor prognosis [ 16 ]. In colorectal cancer high CD47 expression was linked with poor prognosis, whilst the high presence of SIRPα macrophages was linked with a favorable outcome [ 17 ].…”