Anti-CD47 antibody synergizes with cisplatin against laryngeal cancer by enhancing phagocytic ability of macrophages

Abstract

Cisplatin is mainly used in late-stage or recurrent laryngeal cancer patients. However, the effect of the chemotherapy is limited due to cisplatin resistance. Therefore, we explored the synergized role of immunosuppressive mediator with cisplatin in laryngeal cancer.Cancer cells isolated from tissues of patients with laryngeal cancer were treated with cisplatin to screen the potential immunosuppressive mediator, whose synergized effects with cisplatin were explored both in vivo and in vitro. CD47 was selected for its high expression in cisplatin-treated laryngeal cancer cells. Blocking CD47 expression using its neutralizing antibody (aCD47) synergized with cisplatin to increase macrophage phagocytosis in a co-culture system of human epithelial type 2 (Hep-2) cancer cells with tumorassociated macrophages (TAMs). Moreover, aCD47 together with cisplatin prevented tumor growth by inhibiting proliferation of cancer cells and the secretion of proinflammatory cytokines, as well as by inducing the apoptosis of cancer cells and phagocytosis of TAMs in a Hep-2-implanted mouse tumor model. aCD47 synergized with cisplatin against laryngeal cancer by enhancing the phagocytic ability of TAMs, and the combined therapy of cisplatin and aCD47 might serve as a novel therapeutic strategy against laryngeal cancer.

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“…IgG4 showed slightly weaker binding to Fc receptors on immune cells, which may compromise the potency but enhance protection against CD47-expressing nontumor cells. 468 was developed by ALX Oncology and contains two SIRPα high-affinity CD47 binding domains linked to the inactive Fc domain of human immunoglobulins. Its Fc domain has been reengineered to inhibit Fcγ receptors.…”

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“…The inhibition of HDAC or PI3Kγ exerted anti-tumor effects by downregulating M2 and upregulating M1 molecules ( 222 ). CD47 also affects TAMs polarization, and the anti-CD47 antibody increased the ability of macrophages to phagocytose tumor cells by blocking the interaction of CD47 with SIRPα on macrophages, which has been demonstrated in various preclinical models of solid tumors ( 229 , 230 ). In addition, the suppression effect of macrophages can be abolished by inhibiting monocyte recruitment and localization to tumor tissue by targeting macrophage chemokines or their receptors (e.g., chemokine 2, chemokine 5, and CSF-1R).…”