Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

Abstract

In the past 25 years, a considerable number of therapeutic monoclonal antibodies (mAb) against a variety of tumor-associated antigens (TAA) have become available for the targeted treatment of hematologic and solid cancers. Such antibodies opsonize cancer cells and can trigger cytotoxic responses mediated by Fc-receptor expressing immune cells in the tumor microenvironment (TME). Although frequently ignored, neutrophils, which are abundantly present in the circulation and many cancers, have demonstrated to constitute bona fide effector cells for antibody-mediated tumor elimination in vivo. It has now also been established that neutrophils exert a unique mechanism of cytotoxicity towards antibody-opsonized tumor cells, known as trogoptosis, which involves Fc-receptor (FcR)-mediated trogocytosis of cancer cell plasma membrane leading to a lytic/necrotic type of cell death. However, neutrophils prominently express the myeloid inhibitory receptor SIRPα, which upon interaction with the ‘don’t eat me’ signal CD47 on cancer cells, limits cytotoxicity, forming a mechanism of resistance towards anti-cancer antibody therapeutics. In fact, tumor cells often overexpress CD47, thereby even more strongly restricting neutrophil-mediated tumor killing. Blocking the CD47-SIRPα interaction may therefore potentiate neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) towards cancer cells, and various inhibitors of the CD47-SIRPα axis are now in clinical studies. Here, we review the role of neutrophils in antibody therapy in cancer and their regulation by the CD47-SIRPα innate immune checkpoint. Moreover, initial results of CD47-SIRPα blockade in clinical trials are discussed.

Neutrophils as immune effector cells in antibody therapy in cancer

“…However, additional treatment with sodium stibogluconate, significantly enhanced tumor cell elimination by neutrophils. Currently, initial clinical trials with various CD47‐SIRPα blockers have been conducted in both hematological and solid cancers (discussed in detail in ref 230 …”

“…Also in these patients, toxicity was limited to grade I and II adverse events and two patients with fallopian tube cancer achieved partial remission. Currently, at least 37 CD47‐SIRPα blocking compounds have entered the clinical phase in over 102 clinical trials, further demonstrating the great interest and potential in this field 230 . Recently, evidence emerged that CD47‐SIRPα blockade may promote adaptive immunity.…”

“…The best example is the signal regulatory protein (SIRP) α and CD47 axis. 230 SIRPα is an inhibitory receptor expressed on myeloid cells, including neutrophils, macrophages, and subpopulations of DCs. CD47 is expressed on virtually all cells in the body and induces a "don't eat me" signal in myeloid cells by interacting with SIRPα.…”

“…Currently, at least 37 CD47-SIRPα blocking compounds have entered the clinical phase in over 102 clinical trials, further demonstrating the great interest and potential in this field. 230 Recently, evidence emerged that CD47-SIRPα blockade may promote adaptive immunity. Macrophages were co-cultured with K562 cells expressing both EGFR and the viral protein CMVpp65, and treated with a CD47xEGFR-IgG1 BsAb.…”

BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells

“…35 Around 35 therapeutics directed towards the CD47-SIRPα axis have entered clinical trials in recent years. [36][37][38] The first clinical studies were performed with CD47targeting agents, used as single agents or in combination with anti-TAAs or anti-PD-1, and have shown limited toxicity and promising initial efficacy. 36 37 39-41 However, conceptually there appear to be several disadvantages of targeting CD47 per se.…”