CD47/SIRPα axis: bridging innate and adaptive immunity

Abstract

Myeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact anticancer immune responses. One way of inhibiting the positive contributions of myeloid cells is by signaling through the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) axis. The SIRPα receptor is expressed on myeloid cells and is an inhibitory immune receptor that, upon binding to CD47 protein, delivers a 'don't eat me' signal. As CD47 is often overexpressed on cancer cells, treatments targeting CD47/SIRPα have been under active investigation and are currently being tested in clinical settings. Interestingly, the CD47/SIRPα axis is also involved in T cell-mediated antitumor responses. In this perspective we provide an overview of recent studies showing how therapeutic blockade of the CD47/SIRPα axis improves the adaptive immune response. Furthermore, we discuss the interconnection between the myeloid CD47/SIRPα axis and adaptive T cell responses as well as the potential therapeutic role of the CD47/SIRPα axis in tumors with acquired resistance to the classic immunotherapy through major histocompatibility complex downregulation. Altogether this review provides a profound insight for the optimal exploitation of CD47/SIRPα immune checkpoint therapy.

Keywords: adaptive immunity; immunity, innate; immunotherapy; macrophages; phagocytosis.

Figure 1

CD47/SIRPα blockade indirectly enhances T cell responses through myeloid cells. CD47/SIRPα blockade enhances T cell responses through (upper right) the cross-priming and maturation abilities of DCs and production of T cell response promoting cytokines and chemokines, and (lower right) the cross-presentation and chemokine production of macrophages. While trogoptosis by neutrophils (lower left) and ADCC by NK cells (upper left) is promoted through CD47/SIRPα blockade, it is unknown whether this affects T cell responses directly. Figure created with BioRender.com. ADCC, antibody-mediated cellular toxicity; CD47, cluster of differentiation 47; DCs, dendritic cells; NK, natural killer; SIRPα, signal regulatory protein alpha.

Figure 2

Expression of pGlu-CD47 and pan-CD47 on CD4+ OVA-specific T cells during an immune response. Pan-CD47 expression does not alter during the immune response, while pGlu-CD47 surface levels decrease during the proliferation phase. Only a small proportion of cells maintain pGlu-CD47, which gives rise to memory T cells. Figure created with BioRender.com. CD, cluster of differentiation; OVA, ovalbumin.

Figure 3

MHC-I-deficient tumors are sensitized to CD47/SIRPα blockade. The inhibitory receptor LILRB1, which binds surface MHC I, shows synergy with other inhibitory receptor pathways, including the CD47/SIRPα axis. Figure created with BioRender.com. CD47, cluster of differentiation 47; LILRB1, Leukocyte immunoglobulin-like receptor subfamily B member 1; MHC-I, major histocompatibility complex I; SIRPα, signal regulatory protein alpha.