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Phagocytosis checkpoints as new targets for cancer immunotherapy

Abstract

Cancer immunotherapies targeting adaptive immune checkpoints have substantially improved patient outcomes across multiple metastatic and treatment-refractory cancer types. However, emerging studies have demonstrated that innate immune checkpoints, which interfere with the detection and clearance of malignant cells through phagocytosis and suppress innate immune sensing, also have a key role in tumour-mediated immune escape and might, therefore, be potential targets for cancer immunotherapy. Indeed, preclinical studies and early clinical data have established the promise of targeting phagocytosis checkpoints, such as the CD47–signal-regulatory protein α (SIRPα) axis, either alone or in combination with other cancer therapies. In this Review, we highlight the current understanding of how cancer cells evade the immune system by disrupting phagocytic clearance and the effect of phagocytosis checkpoint blockade on induction of antitumour immune responses. Given the role of innate immune cells in priming adaptive immune responses, an improved understanding of the tumour-intrinsic processes that inhibit essential immune surveillance processes, such as phagocytosis and innate immune sensing, could pave the way for the development of highly effective combination immunotherapy strategies that modulate both innate and adaptive antitumour immune responses.

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Fig. 1: Regulation of tumour cell phagocytosis.
Fig. 2: History of phagocytosis checkpoint blockade in cancer.
Fig. 3: Phagocytosis and innate immune-sensing pathway activation.
Fig. 4: Bridging innate and adaptive antitumour immunity.
Fig. 5: Combination therapy with phagocytosis checkpoint blockade.

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Acknowledgements

This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RR180017) (W.J.), The National Cancer Institute (K08CA241070) (W.J.), the National Institute of Neurological Disorders and Stroke (Grant R01 NS104315) (B.Y.S.K.), the National Cancer Institute Pathway to Independence Award (R00CA201075) (M.F.), the Damon Runyon–Dale F. Frey Award for Breakthrough Scientists (DFS-22-16) (M.F.) and the V Foundation for Cancer Research V Scholar Award (V2018-012) (M.F.). The authors thank J. Feinberg (The University of Texas Southwestern Medical Centre, Department of Radiation Oncology) for editorial assistance.

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Contributions

W.J. and M.F. researched data for the article. W.J., M.F., B.Y.S.K., C.C.Z., Y.-X. F. and I.L.W. made substantial contributions to the discussion of content. All authors wrote the manuscript, and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Mingye Feng or Wen Jiang.

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Competing interests

I.L.W. is a co-founder and director of, holds equity in and has multiple patents licensed to Forty Seven Inc. M.F. declares patent applications pertaining to stimulating TLR/BTK signalling to promote calreticulin in macrophages (assigned to the Stanford University) and holds equity with Forty Seven Inc. The other authors declare no competing interests. C.C.Z. is a scientific founder of, holds equity in and has multiple patents licensed to Immune-Onc Therapeutics.

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Nature Reviews Cancer thanks E. Bremer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Innate immune system

A major branch of the immune system that provides non-specific defence against pathogens immediately after insult or against transformed cells; the innate immune system is also responsible for educating the adaptive immune system through cross-priming.

Antigen-presenting cells

(APCs). A collection of different immune cell populations that activate cellular immune responses by processing and presenting antigens that can be recognized by T cells; classical professional APCs include dendritic cells and macrophages.

Adaptive immune system

A major branch of the immune system that comprises highly specialized immune cell populations that recognize specific antigens to produce immune-memory responses.

Major histocompatibility complex class I

(MHC-I). A complex of cell membrane proteins that is expressed by all nucleated cells to present antigens to be recognized by T cells.

Tumour-associated macrophages

(TAMs). A class of macrophage found in high abundance in certain solid tumours that are often associated with immune-suppressive properties within the tumour microenvironment.

Fc domain

The stem region of an antibody that interacts with the cell-surface-bound Fc receptors and proteins of the complement system.

Cytotoxic T lymphocyte exhaustion

A state of dysfunction in cytotoxic T cells during chronic infections or inflammation that is defined by diminished effector function, increased activation of inhibitory signals and, subsequently, progressive loss of the antigen-specific T cells.

Damage-associated molecular patterns

(DAMPs). Host-cell-derived biomolecules that can be recognized by pattern recognition receptors to initiate inflammatory responses.

Antibody-dependent cellular cytotoxicity

(ADCC). A mechanism of cell-mediated immune defence whereby an immune effector cell attacks and lyses a target cell coated by antibodies that recognize specific cell-membrane antigens.

Antibody-dependent cellular phagocytosis

(ADCP). A process in which antibody-opsonized target cells activate the Fc receptors expressed on the surface of macrophages, resulting in the phagocytosis of the target cells.

Trogoptosis

A process in which the lysis of antibody-opsonized tumour cells occurs by neutrophils, resulting in the mechanical disruption of the cancer cell plasma membrane, leading to cell death.

Reticulocytosis

An increase in reticulocytes (immature red blood cells) due to an increase in the activity of the bone marrow to replace red blood cell loss, as in the setting of blood loss or anaemia.

Pathogen-associated molecular patterns

(PAMPs). Small molecular motifs derived from microorganisms that can be recognized by specialized pattern recognition receptors.

Phagolysosomes

Cytoplasmic vesicular bodies formed by the fusion of a phagosome with a lysosome during the phagocytosis process.

Micronuclei

Often an indicator of a genotoxic event or chromosomal instability, a micronuclei is a small nucleus that forms whenever a chromosome or its fragment is not incorporated into one of the daughter nuclei during cell division.

Chromothripsis

A processes in which chromosomes fragment into many pieces and are then stitched back together in a random fashion through DNA repair, resulting in a highly unstable chromosome from a single catastrophic event.

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Feng, M., Jiang, W., Kim, B.Y.S. et al. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer 19, 568–586 (2019). https://doi.org/10.1038/s41568-019-0183-z

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