The CD47–SIRPα pathway in cancer immune evasion and potential therapeutic implications

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Multiple lines of investigation have demonstrated that the immune system plays an important role in preventing tumor initiation and controlling tumor growth. Accordingly, many cancers have evolved diverse mechanisms to evade such monitoring. While multiple immune cell types mediate tumor surveillance, recent evidence demonstrates that macrophages, and other phagocytic cells, play a key role in regulating tumor growth through phagocytic clearance. In this review we highlight the role of tumor immune evasion through the inhibition of phagocytosis, specifically through the CD47–signal-regulatory protein-α pathway, and discuss how targeting this pathway might lead to more effective cancer immunotherapies.

Highlights

Phagocytic cells, macrophages, regulate tumor growth through phagocytic clearance. ► CD47 binds SIRPα on phagocytes which delivers an inhibitory signal for phagocytosis. ► A blocking anti-CD47 antibody enabled phagocytic clearance of many human cancers. ► Phagocytosis depends on a balance of anti-(CD47) and pro-(calreticulin) signals. ► Anti-CD47 antibody synergized with an FcR-engaging antibody, such as rituximab.

Introduction

The initiation and perpetuation of cancer depends on several hallmark features including sustained proliferation, inhibition of growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion, and evading immune destruction [1]. The concept of tumor immune surveillance, the identification and elimination of cancer cells by the immune system was first discussed over a century ago, and since then multiple immune system components have been implicated [2]. While the adaptive immune response is well recognized to play an important role in anti-tumor immunity, the innate immune system, specifically the macrophage, has only recently been shown to play a prominent role in regulating tumor pathogenesis as well [3]. Macrophages exhibit functions including phagocytosis, antigen presentation, and cytokine production, which play roles in homeostatic cell clearance, pathogen defense, and inflammatory responses. Beginning in the 1970s, it was found that tumor growth could be promoted by tumor-associated macrophages (TAMs) [4]. In the last two decades, these TAMs have been subdivided into two distinct macrophage subpopulations, which promote either a pro-tumorigenic or anti-tumorigenic environment depending on their capacity to present antigens, produce inflammatory cytokines, stimulate angiogenesis, and enable cytotoxic activity (reviewed in [5]). While cytokine production and antigen presentation by macrophages have been shown to impact tumor growth, the role of macrophage phagocytosis in tumor pathogenesis has been relatively unexplored. In physiologic settings, macrophage phagocytosis is crucial to programmed cell removal in clearing damaged and foreign cells. This phagocytic engulfment depends on the relative expression of pro-phagocytic and anti-phagocytic signals on the target cell. Most notably, during apoptosis, expression of pro-phagocytic signals and loss of anti-phagocytic signals leads to engulfment (reviewed in [6]). Recent data have demonstrated that tumors evade macrophage phagocytosis through the expression of anti-phagocytic signals, including CD200 and CD47 [6]. This review will focus on the role of the CD47–signal-regulatory protein-alpha (SIRPα) pathway in tumor pathogenesis and potential therapeutic strategies targeting this pathway.

Section snippets

The immunoregulatory role of CD47 in human malignancies

CD47 is a cell surface molecule in the immunoglobulin superfamily that binds several proteins including integrins [7] and thrombospondin-1 [8], and has been implicated in diverse physiologic processes including cell migration [9, 10, 11], T cell and dendritic cell (DC) activation [12], and axon development [13]. In addition, CD47 functions as an inhibitor of phagocytosis through ligation of SIRPα expressed on phagocytes, leading to tyrosine phosphatase activation and inhibition of myosin

Therapeutic targeting of CD47 in human cancers

The increased expression of CD47 on many different human tumor types, and its known function as a ‘don’t eat me’ signal, suggests the potential for targeting the CD47–SIRPα pathway as a common therapy for human malignancies. Efforts have been made to develop therapies inhibiting the CD47–SIRPα pathway, principally through blocking monoclonal antibodies directed against CD47, and also possibly with a recombinant SIRPα protein that can also bind and block CD47 (Figure 1). Anti-CD47 antibodies

Selective targeting of tumor cells by anti-CD47 antibody can be mediated by the CD47-calreticulin phagocytosis axis

While CD47 is expressed on both tumor cells and many normal cell types, we showed that a blocking anti-CD47 antibody selectively eliminates tumor cells, but not their normal counterparts [21••, 22, 23••, 30••]. In addition, administration of anti-mouse CD47 antibodies to wild type mice for weeks did not result in any severe toxicity (data not shown) [21••]. Moreover, inhibition of mouse CD47 with an antibody or morphilino conferred radioprotection to normal tissues [42]. These results suggest

Combination strategies targeting CD47 in cancer

While monotherapies targeting CD47 were efficacious in several preclinical tumor models, combination strategies involving inhibition of the CD47–SIRPα pathway offer even greater therapeutic potential. Specifically, antibodies targeting CD47–SIRPα can be included in combination therapies with other therapeutic antibodies, macrophage-enhancing agents, chemo-radiation therapy, or as an adjuvant therapy to inhibit metastasis (Figure 2).

First, a blocking anti-CD47 antibody can be combined with

Conclusion

Evasion of immune recognition is a major mechanism by which cancers establish and propagate disease. Recent data have demonstrated that the innate immune system plays a key role in modulating tumor phagocytosis through the CD47–SIRPα pathway. Therapeutic approaches inhibiting this pathway have demonstrated significant efficacy, leading to the reduction and elimination of multiple tumor types in preclinical models through several distinct mechanisms, most notably phagocytosis. While initial

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work is supported by the Ludwig Foundation and grants from the NIH (I.L.W.). R.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. M.P.C., R.M., and I.L.W. have filed U.S. Patent Application Serial No. 12/321,215 entitled ‘Methods For Manipulating Phagocytosis Mediated by CD47.’

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