Lack of SIRP‐alpha reduces lung cancer growth in mice by promoting anti‐tumour ability of macrophages and neutrophils

Abstract

Objectives: Signal regulatory protein-alpha (SIRPα) is a transmembrane glycoprotein specifically expressed on myeloid cells. Blockade of SIRPα/CD47 interaction is effective in combinational therapy of some cancers. This study aimed to explore into the role and underlying molecular mechanisms of SIRPα in lung cancer growth. Materials and Methods: A mouse model with lung cancer in wild-type (WT) and SIRPα-knockout mouse (KO) mice was established by subcutaneous injection of Lewis murine lung cancer cells (LLC). Circulating monocytes and neutrophils were depleted in mice by intraperitoneal administration of clodronate liposomes and anti-Ly6G antibody, respectively. Phenotypes and phagocytosis of macrophages and neutrophils were analysed by flow cytometry. Transwell assay was used to analyse LLC cells migration and invasion. Results: Lack of SIRPα inhibited LLC cells growth in KO mice, associated with reduced infiltrating PD-1 + CD8 + T cells and production of IL-6 from infiltrating macrophages and neutrophils in tumour tissues. Depletion of circulating monocytes and neutrophils reduced LLC cells growth in WT mice, which was abolished in KO mice. Studies in vitro showed that lack of SIRPα increased M1/M2 ratio, and reduced LLC cell migration and invasion via attenuated IL-6 secretion. Lack of SIRPα expression in neutrophils effectively increased the cytotoxic activity to LLC cells in vitro. Conclusions: Lack of SIRPα suppressed lung cancer cell growth in mice, dependent on circulating macrophages and neutrophils, in association with improved phagocytosis and reduced IL-6 expression. | INTRODUCTIONLung cancer ranks first in mortality and second in the prevalence of malignant cancer worldwide in 2021. 1 To date, targeting immune checkpoints such as programmed death-1 (PD-1), and cytolytic T lymphocyte-associated antigen-4 (CTLA-4), have become effective therapeutic approaches among some lung cancer patients. 2,3 However, cohorts of patients have developed immune resistance to the immune checkpoint inhibitors (ICIs), due to infiltration of tumourassociated macrophages and neutrophils (TAMs and TANs), immunosuppressive myeloid cells and induction of T cell exclusion. [4][5][6] In addition, IL-6 is up-regulated in most of tumour patients and plays an important role in the modulation of these immunosuppressive cells. 7,8 It was previously reported that the combined blockade of IL-6 and Linyue Pan and Bin Wang contributed equally to this study.

Microglia Promote Inhibitory Synapse Phagocytosis in the Spinal Cord Dorsal Horn and Modulate Pain-Like Behaviors in a Murine Cancer-Induced Bone Pain Model

“…38 On CD47-SIRPα blockade, it elicits a prophagocytic signal to potentiate tumor control via increasing tumor cell phagocytosis, which has emerged as a novel immune checkpoint inhibitor in various cancer patients. 39 Moreover, the decreased SIRPα level has been discovered in some patients diagnosed with malignancies. 40 According to our experiment, it is worth noting that the declined SIRPα signal might induce excessive synaptic clearance in microglia towards GABAergic synapse in the central nervous system in the murine bone cancer pain model, which is in conjunction with their pain-related behavior.…”

Cisplatin‐induced oxPAPC release enhances MDSCs infiltration into LL2 tumour tissues through MCP‐1/CCL2 and LTB4/LTB4R pathways

“…28 Previous study pointed that suppressing lung cancer cell growth in mice is dependent on circulating macrophages and neutrophils. 29 Macrophages are one of the primary cell types that drive the production of MCP-1 and LTB4. 26,30 A previous study showed a parallel increase of Galectin-3 level and the number of MDSCs in mice after cisplatin treatment, 31 which provokes our interest.…”

“…Among the many chemokines or cytokines, MCP‐1 is a vital monocyte‐attracting chemokine with strong chemotaxis activity, and potently recruits blood monocytes to inflammatory or tumour sites 26,27 ; LTB4 is a chemokine with a strong effect on neutrophils, playing an important role in the chemotaxis and infiltration of neutrophils 28 . Previous study pointed that suppressing lung cancer cell growth in mice is dependent on circulating macrophages and neutrophils 29 . Macrophages are one of the primary cell types that drive the production of MCP‐1 and LTB4 26,30 …”

“… 28 Previous study pointed that suppressing lung cancer cell growth in mice is dependent on circulating macrophages and neutrophils. 29 Macrophages are one of the primary cell types that drive the production of MCP‐1 and LTB4. 26 , 30 …”

CD47 blockade enhances phagocytosis of cardiac cell debris by neutrophils

“…Inhibition of this interaction leads to an increasing phagocytosis of tumor cells by macrophages [12] , [16] , [18] . SIRP- α deficiency also enhances phagocytotic activity of neutrophils during lung cancer [19] . In the context of repAMI it was also shown that inhibition of CD47 enhances phagocytosis of cardiac cell debris by macrophages leading to a reduced infarction area [20] .…”