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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Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Carbone, D. P. et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017).
Balar, A. V. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).
Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017).
Morris, V. K. et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18, 446–453 (2017).
Sharma, P. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 18, 312–322 (2017).
Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).
Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).
Nghiem, P. T. et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N. Engl. J. Med. 374, 2542–2552 (2016).
Darvin, P., Toor, S. M., Sasidharan Nair, V. & Elkord, E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp. Mol. Med. 50, 165 (2018).
Ribas, A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015).
Simeone, E. & Ascierto, P. A. Anti-PD-1 and PD-L1 antibodies in metastatic melanoma. Melanoma Manag. 4, 175–178 (2017).
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).
Tawbi, H. A. et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N. Engl. J. Med. 379, 722–730 (2018).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N.Engl. J. Med. 378, 2093–2104 (2018).
Wrangle, J. M. et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 19, 694–704 (2018).
Gotwals, P. et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat. Rev. Cancer 17, 286–301 (2017).
Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).
Morvan, M. G. & Lanier, L. L. NK cells and cancer: you can teach innate cells new tricks. Nat. Rev. Cancer 16, 7–19 (2016).
Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).
Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11–22 (2004).
Jutras, I. & Desjardins, M. Phagocytosis: at the crossroads of innate and adaptive immunity. Annu. Rev. Cell Dev. Biol. 21, 511–527 (2005).
Oldenborg, P. A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000). This important study shows, for the first time, the function of CD47 on RBCs as a ‘marker of self’ by interacting with SIRPα and inhibiting macrophage activity.
Barclay, A. N. & Van den Berg, T. K. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu. Rev. Immunol. 32, 25–50 (2014).
Medzhitov, R. & Janeway, C. A. Jr. Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300 (2002).
Chao, M. P., Weissman, I. L. & Majeti, R. The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr. Opin. Immunol. 24, 225–232 (2012).
Kharitonenkov, A. et al. A family of proteins that inhibit signalling through tyrosine kinase receptors. Nature 386, 181–186 (1997). This study identifies the SIRP family and their function in binding to SH2-domain-containing phosphotyrosine phosphatases for signal transduction.
Fujioka, Y. et al. A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Mol. Cell. Biol. 16, 6887–6899 (1996).
Veillette, A., Thibaudeau, E. & Latour, S. High expression of inhibitory receptor SHPS-1 and its association with protein-tyrosine phosphatase SHP-1 in macrophages. J. Biol. Chem. 273, 22719–22728 (1998).
Seiffert, M. et al. Signal-regulatory protein alpha (SIRPα) but not SIRPβ is involved in T-cell activation, binds to CD47 with high affinity, and is expressed on immature CD34+CD38– hematopoietic cells. Blood 97, 2741–2749 (2001).
Ichigotani, Y. et al. Molecular cloning of a novel human gene (SIRP-B2) which encodes a new member of the SIRP/SHPS-1 protein family. J. Hum. Genet. 45, 378–382 (2000).
Barclay, A. N. & Brown, M. H. The SIRP family of receptors and immune regulation. Nat. Rev. Immunol. 6, 457–464 (2006).
Dietrich, J., Cella, M., Seiffert, M., Buhring, H. J. & Colonna, M. Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells. J. Immunol. 164, 9–12 (2000).
Tomasello, E. et al. Association of signal-regulatory proteins beta with KARAP/DAP-12. Eur. J. Immunol. 30, 2147–2156 (2000).
Brooke, G., Holbrook, J. D., Brown, M. H. & Barclay, A. N. Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family. J. Immunol. 173, 2562–2570 (2004).
Brown, E., Hooper, L., Ho, T. & Gresham, H. Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins. J. Cell Biol. 111, 2785–2794 (1990).
Campbell, I. G., Freemont, P. S., Foulkes, W. & Trowsdale, J. An ovarian tumor marker with homology to vaccinia virus contains an IgV-like region and multiple transmembrane domains. Cancer Res. 52, 5416–5420 (1992).
Brown, E. J. & Frazier, W. A. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 11, 130–135 (2001).
Seiffert, M. et al. Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. Blood 94, 3633–3643 (1999).
Jiang, P., Lagenaur, C. F. & Narayanan, V. Integrin-associated protein is a ligand for the P84 neural adhesion molecule. J. Biol. Chem. 274, 559–562 (1999).
Han, X. et al. CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation. J. Biol. Chem. 275, 37984–37992 (2000).
Vernon-Wilson, E. F. et al. CD47 is a ligand for rat macrophage membrane signal regulatory protein SIRP (OX41) and human SIRPα 1. Eur. J. Immunol. 30, 2130–2137 (2000).
Noguchi, T. et al. Characterization of a 115-kDa protein that binds to SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in Chinese hamster ovary cells. J. Biol. Chem. 271, 27652–27658 (1996).
Neel, B. G., Gu, H. & Pao, L. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).
Tsai, R. K. & Discher, D. E. Inhibition of ‘self’ engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J. Cell Biol. 180, 989–1003 (2008).
Rebres, R. A., Vaz, L. E., Green, J. M. & Brown, E. J. Normal ligand binding and signaling by CD47 (integrin-associated protein) requires a long range disulfide bond between the extracellular and membrane-spanning domains. J. Biol. Chem. 276, 34607–34616 (2001).
Logtenberg, M. E. W. et al. Glutaminyl cyclase is an enzymatic modifier of the CD47– SIRPα axis and a target for cancer immunotherapy. Nat. Med. 25, 612–619 (2019).
Cameron, C. M., Barrett, J. W., Mann, M., Lucas, A. & McFadden, G. Myxoma virus M128L is expressed as a cell surface CD47-like virulence factor that contributes to the downregulation of macrophage activation in vivo. Virology 337, 55–67 (2005).
Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009). This study identifies CD47 as a ‘don’t eat me’ signal on cancer cells for their self-protection, and revealed the therapeutic potential of CD47-blocking agents in inducing the antitumour effects of macrophages.
Willingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPα) interaction is a therapeutic target for human solid tumors. Proc. Natl Acad. Sci. USA 109, 6662–6667 (2012). This study examines the expression of CD47 in a wide range of solid tumour cells and evaluates the anticancer effects of CD47-blocking antibodies in multiple preclinical solid tumour models.
Wang, Y. et al. Intravenous delivery of siRNA targeting CD47 effectively inhibits melanoma tumor growth and lung metastasis. Mol. Ther. 21, 1919–1929 (2013).
Chan, K. S. et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc. Natl Acad. Sci. USA 106, 14016–14021 (2009).
Feng, M. et al. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc. Natl Acad. Sci. USA 112, 2145–2150 (2015).
Weiskopf, K. et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J. Clin. Invest. 126, 2610–2620 (2016).
Betancur, P. A. et al. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. Nat. Commun. 8, 14802 (2017).
Zhang, H. et al. HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc. Natl Acad. Sci. USA 112, E6215–E6223 (2015).
Liu, F. et al. BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma. Oncotarget 8, 69477–69492 (2017).
Casey, S. C. et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352, 227–231 (2016).
Ishida, Y., Agata, Y., Shibahara, K. & Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992).
Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).
Sanmamed, M. F. & Chen, L. Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J. 20, 256–261 (2014).
Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012). This article is an important review summarizing the progress in identifying immune checkpoints in cancer and blocking them as a cancer immunotherapy approach.
Baumeister, S. H., Freeman, G. J., Dranoff, G. & Sharpe, A. H. Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Immunol 34, 539–573 (2016).
Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).
Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).
Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).
Barkal, A. A. et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat. Immunol. 19, 76–84 (2018).
Li, B. et al. Tumor-derived exosomal HMGB1 promotes esophageal squamous cell carcinoma progression through inducing PD1+ TAM expansion. Oncogenesis 8, 17 (2019).
Rock, K. L., Reits, E. & Neefjes, J. Present yourself! By MHC class I and MHC class II molecules. Trends Immunol. 37, 724–737 (2016).
Borges, L., Hsu, M. L., Fanger, N., Kubin, M. & Cosman, D. A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J. Immunol. 159, 5192–5196 (1997).
Colonna, M. et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J. Exp. Med. 186, 1809–1818 (1997).
Samaridis, J. & Colonna, M. Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: structural evidence for new stimulatory and inhibitory pathways. Eur. J. Immunol. 27, 660–665 (1997).
Katz, H. R. Inhibition of inflammatory responses by leukocyte Ig-like receptors. Adv. Immunol. 91, 251–272 (2006).
Hunt, J. S. et al. HLA-G in reproduction: studies on the maternal–fetal interface. Hum. Immunol. 61, 1113–1117 (2000).
Tedla, N., Lee, C. W., Borges, L., Geczy, C. L. & Arm, J. P. Differential expression of leukocyte immunoglobulin-like receptors on cord-blood-derived human mast cell progenitors and mature mast cells. J. Leukoc. Biol. 83, 334–343 (2008).
Mori, Y. et al. Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development. J. Immunol. 181, 4742–4751 (2008).
Festenstein, H. & Garrido, F. MHC antigens and malignancy. Nature 322, 502–503 (1986).
Leone, P. et al. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J. Natl Cancer Inst. 105, 1172–1187 (2013).
Garrido, F., Ruiz-Cabello, F. & Aptsiauri, N. Rejection versus escape: the tumor MHC dilemma. Cancer Immunol. Immunother. 66, 259–271 (2017).
Colonna, M. et al. Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J. Immunol. 160, 3096–3100 (1998).
Zheng, J. et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656–660 (2012).
Fanger, N. A. et al. The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. Eur. J. Immunol. 28, 3423–3434 (1998).
Lu, N. et al. Human semaphorin-4A drives Th2 responses by binding to receptor ILT-4. Nat. Commun. 9, 742 (2018).
Manavalan, J. S. et al. Alloantigen specific CD8+CD28– FOXP3+ T suppressor cells induce ILT3+ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity. Int. Immunol. 16, 1055–1068 (2004).
Chen, H. M. et al. Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity. J. Clin. Invest. 128, 5647–5662 (2018).
Jones, D. C. et al. HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding. J. Immunol. 186, 2990–2997 (2011).
Cella, M. et al. A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing. J. Exp. Med. 185, 1743–1751 (1997).
Deng, M. et al. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature 562, 605–609 (2018).
John, S. et al. A novel anti-LILRB4 CAR-T cell for the treatment of monocytic AML. Mol. Ther. 26, 2487–2495 (2018).
Inui, M. et al. Tolerogenic immunoreceptor ILT3/LILRB4 paradoxically marks pathogenic auto-antibody-producing plasmablasts and plasma cells in non-treated SLE. Int. Immunol. 28, 597–604 (2016).
Ulges, A. et al. Protein kinase CK2 enables regulatory T cells to suppress excessive TH2 responses in vivo. Nat. Immunol. 16, 267–275 (2015).
van der Touw, W., Chen, H. M., Pan, P. Y. & Chen, S. H. LILRB receptor-mediated regulation of myeloid cell maturation and function. Cancer Immunol. Immunother. 66, 1079–1087 (2017).
Kang, X. et al. Inhibitory leukocyte immunoglobulin-like receptors: immune checkpoint proteins and tumor sustaining factors. Cell Cycle 15, 25–40 (2016).
de Goeje, P. L. et al. Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer. Oncoimmunology 4, e1014242 (2015).
Chang, C. C. et al. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat. Immunol. 3, 237–243 (2002).
Suciu-Foca, N. et al. Soluble Ig-like transcript 3 inhibits tumor allograft rejection in humanized SCID mice and T cell responses in cancer patients. J. Immunol. 178, 7432–7441 (2007).
Xu, Z. et al. ILT3.Fc-CD166 interaction induces inactivation of p70 S6 kinase and inhibits tumor cell growth. J. Immunol. 200, 1207–1219 (2018).
Zhang, Q. & Salter, R. D. Distinct patterns of folding and interactions with calnexin and calreticulin in human class I MHC proteins with altered N-glycosylation. J. Immunol. 160, 831–837 (1998).
Harris, M. R., Yu, Y. Y., Kindle, C. S., Hansen, T. H. & Solheim, J. C. Calreticulin and calnexin interact with different protein and glycan determinants during the assembly of MHC class I. J. Immunol. 160, 5404–5409 (1998).
Krause, K. H. & Michalak, M. Calreticulin. Cell 88, 439–443 (1997).
Basu, S., Binder, R. J., Ramalingam, T. & Srivastava, P. K. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14, 303–313 (2001).
Ogden, C. A. et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781–795 (2001).
Vandivier, R. W. et al. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J. Immunol. 169, 3978–3986 (2002).
Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007). This classical study identifies the process of immunogenic cell death.
Obeid, M. et al. Ecto-calreticulin in immunogenic chemotherapy. Immunol. Rev. 220, 22–34 (2007).
Obeid, M. et al. Leveraging the immune system during chemotherapy: moving calreticulin to the cell surface converts apoptotic death from ‘silent’ to immunogenic. Cancer Res. 67, 7941–7944 (2007).
Panaretakis, T. et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ. 15, 1499–1509 (2008).
Krysko, D. V. et al. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860–875 (2012).
Garg, A. D. et al. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim. Biophys. Acta 1805, 53–71 (2010).
Pang, W. W. et al. Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc. Natl Acad. Sci. USA 110, 3011–3016 (2013).
Chao, M. P. et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94 (2010).
Lagasse, E. & Weissman, I. L. bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages. J. Exp. Med. 179, 1047–1052 (1994).
Chao, M. P., Majeti, R. & Weissman, I. L. Programmed cell removal: a new obstacle in the road to developing cancer. Nat. Rev. Cancer 12, 58–67 (2011).
Byrne, J. C. et al. Bruton’s tyrosine kinase is required for apoptotic cell uptake via regulating the phosphorylation and localization of calreticulin. J. Immunol. 190, 5207–5215 (2013).
Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).
Feng, M. et al. Programmed cell removal by calreticulin in tissue homeostasis and cancer. Nat. Commun. 9, 3194 (2018).
Duvall, E., Wyllie, A. H. & Morris, R. G. Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunology 56, 351–358 (1985).
Witting, A., Muller, P., Herrmann, A., Kettenmann, H. & Nolte, C. Phagocytic clearance of apoptotic neurons by microglia/brain macrophages in vitro: involvement of lectin-, integrin-, and phosphatidylserine-mediated recognition. J. Neurochem. 75, 1060–1070 (2000).
Hakomori, S. Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv. Cancer Res. 52, 257–331 (1989).
Dube, D. H. & Bertozzi, C. R. Glycans in cancer and inflammation—potential for therapeutics and diagnostics. Nat. Rev. Drug Discov. 4, 477–488 (2005).
Shachar, I., Barak, A., Lewinsky, H., Sever, L. & Radomir, L. SLAMF receptors on normal and malignant B cells. Clin. Immunol. 204, 23–30 (2018).
Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).
Miller, J. C. et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888–899 (2012).
Chen, J. et al. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin. Nature 544, 493–497 (2017). This study demonstrates that SLAMF7 is crucial for mediating CD47-blockade-induced phagocytosis of haematological cancer cells by phagocytes.
Aderem, A. & Underhill, D. M. Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17, 593–623 (1999).
Abram, C. L. & Lowell, C. A. The ins and outs of leukocyte integrin signaling. Annu. Rev. Immunol. 27, 339–362 (2009).
He, Y. et al. Cancer cell-expressed SLAMF7 is not required for CD47-mediated phagocytosis. Nat. Commun. 10, 533 (2019).
Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).
Bakema, J. E. & van Egmond, M. Fc receptor-dependent mechanisms of monoclonal antibody therapy of cancer. Curr. Top. Microbiol. Immunol. 382, 373–392 (2014).
Bruhns, P. Properties of mouse and human IgG receptors and their contribution to disease models. Blood 119, 5640–5649 (2012).
Daeron, M. Fc receptor biology. Annu. Rev. Immunol. 15, 203–234 (1997).
Crowley, M. T. et al. A critical role for Syk in signal transduction and phagocytosis mediated by Fcγ receptors on macrophages. J. Exp. Med. 186, 1027–1039 (1997).
Mao, Y. & Finnemann, S. C. Regulation of phagocytosis by Rho GTPases. Small GTPases 6, 89–99 (2015).
Getahun, A. & Cambier, J. C. Of ITIMs, ITAMs, and ITAMis: revisiting immunoglobulin Fc receptor signaling. Immunol. Rev. 268, 66–73 (2015).
Beers, S. A. et al. Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood 115, 5191–5201 (2010).
Bergtold, A., Desai, D. D., Gavhane, A. & Clynes, R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 23, 503–514 (2005).
Budde, P., Bewarder, N., Weinrich, V., Schulzeck, O. & Frey, J. Tyrosine-containing sequence motifs of the human immunoglobulin G receptors FcRIIb1 and FcRIIb2 essential for endocytosis and regulation of calcium flux in B cells. J. Biol. Chem. 269, 30636–30644 (1994).
Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).
Gul, N. & van Egmond, M. Antibody-dependent phagocytosis of tumor cells by macrophages: a potent effector mechanism of monoclonal antibody therapy of cancer. Cancer Res. 75, 5008–5013 (2015).
Gul, N. et al. Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. J. Clin. Invest. 124, 812–823 (2014).
Overdijk, M. B. et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs 7, 311–321 (2015).
Roghanian, A. et al. Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo. Cancer Cell 27, 473–488 (2015).
Golay, J. et al. Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab. Blood 122, 3482–3491 (2013).
Liu, J. et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLOS ONE 10, e0137345 (2015).
Weiskopf, K. et al. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341, 88–91 (2013).
Lin, G. H. Y. et al. TTI-621 (SIRPαFc), a CD47-blocking cancer immunotherapeutic, triggers phagocytosis of lymphoma cells by multiple polarized macrophage subsets. PLOS ONE 12, e0187262 (2017).
Petrova, P. S. et al. TTI-621 (SIRPαFc): a CD47-blocking innate immune checkpoint inhibitor with broad antitumor activity and minimal erythrocyte binding. Clin. Cancer Res. 23, 1068–1079 (2017).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
Chao, M. P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).
Pan, Y. et al. Endoscopic molecular imaging of human bladder cancer using a CD47 antibody. Sci. Transl. Med. 6, 260ra148 (2014).
Wernig, G. et al. Unifying mechanism for different fibrotic diseases. Proc. Natl Acad. Sci. USA 114, 4757–4762 (2017).
Kojima, Y. et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536, 86–90 (2016).
Zhang, M. et al. Anti-CD47 treatment stimulates phagocytosis of glioblastoma by M1 and M2 polarized macrophages and promotes M1 polarized macrophages in vivo. PLOS ONE 11, e0153550 (2016).
Zhao, X. W. et al. CD47-signal regulatory protein-alpha (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction. Proc. Natl Acad. Sci. USA 108, 18342–18347 (2011).
Ring, N. G. et al. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc. Natl Acad. Sci. USA 114, E10578–E10585 (2017).
Matlung, H. L. et al. Neutrophils kill antibody-opsonized cancer cells by trogoptosis. Cell Rep. 23, 3946–3959 (2018).
Advani, R. et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N. Engl. J. Med. 379, 1711–1721 (2018).
Sikic, B. I. et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J. Clin. Oncol. 37, 946–953 (2019).
Brennan, F. R. et al. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs 2, 233–255 (2010).
Mouro-Chanteloup, I. et al. Evidence that the red cell skeleton protein 4.2 interacts with the Rh membrane complex member CD47. Blood 101, 338–344 (2003).
Pandey, S., Kawai, T. & Akira, S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb. Perspect. Biol. 7, a016246 (2014).
Brubaker, S. W., Bonham, K. S., Zanoni, I. & Kagan, J. C. Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol. 33, 257–290 (2015).
Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).
Rakoff-Nahoum, S. & Medzhitov, R. Toll-like receptors and cancer. Nat. Rev. Cancer 9, 57–63 (2009).
Meylan, E., Tschopp, J. & Karin, M. Intracellular pattern recognition receptors in the host response. Nature 442, 39–44 (2006).
Kawai, T. & Akira, S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int. Immunol. 21, 317–337 (2009).
Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016).
Li, T. & Chen, Z. J. The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med. 215, 1287–1299 (2018).
Tseng, D. et al. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc. Natl Acad. Sci. USA 110, 11103–11108 (2013). This is the first study showing that CD47 blockade in tumour cells can improve the efficiency of CD8 + T cell priming by APCs.
Soto-Pantoja, D. R. et al. CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res. 74, 6771–6783 (2014).
Liu, X. et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat. Med. 21, 1209–1215 (2015). This important study demonstrates that the antitumour response mediated by CD47 blockade is dependent on CD8 + T cells and innate immune-sensing pathways in APCs.
Veillette, A. & Chen, J. SIRPα–CD47 immune checkpoint blockade in anticancer therapy. Trends Immunol. 39, 173–184 (2018).
Sockolosky, J. T. et al. Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proc. Natl Acad. Sci. USA 113, E2646–E2654 (2016).
Yi, T. et al. Splenic dendritic cells survey red blood cells for missing self-CD47 to trigger adaptive immune responses. Immunity 43, 764–775 (2015).
Jdey, W., Thierry, S., Popova, T., Stern, M. H. & Dutreix, M. Micronuclei frequency in tumors is a predictive biomarker for genetic instability and sensitivity to the DNA repair inhibitor AsiDNA. Cancer Res. 77, 4207–4216 (2017).
Bakhoum, S. F., Kabeche, L., Murnane, J. P., Zaki, B. I. & Compton, D. A. DNA-damage response during mitosis induces whole-chromosome missegregation. Cancer Discov. 4, 1281–1289 (2014).
Zhang, C. Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015).
Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).
Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).
Xu, M. M. et al. Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein alpha signaling. Immunity 47, 363–373 (2017).
Li, J. et al. Circular DNA: a stable probe for highly efficient mRNA imaging and gene therapy in living cells. Chem. Commun. 54, 896–899 (2018).
Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).
Pereira-Lopes, S. et al. The exonuclease Trex1 restrains macrophage proinflammatory activation. J. Immunol. 191, 6128–6135 (2013).
Piccione, E. C. et al. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. MAbs 7, 946–956 (2015).
Ngo, M. et al. Antibody therapy targeting CD47 and CD271 effectively suppresses melanoma metastasis in patient-derived xenografts. Cell Rep. 16, 1701–1716 (2016).
Bian, Z. et al. CD47–SIRPα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells. Proc. Natl Acad. Sci. USA 113, E5434–E5443 (2016).
Verweij, J. & de Jonge, M. J. Achievements and future of chemotherapy. Eur. J. Cancer 36, 1479–1487 (2000).
George, S., Rini, B. I. & Hammers, H. J. Emerging role of combination immunotherapy in the first-line treatment of advanced renal cell carcinoma: a review. JAMA Oncol. 5, 411–421 (2018).
Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).
Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).
Smyth, M. J., Ngiow, S. F., Ribas, A. & Teng, M. W. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat. Rev. Clin. Oncol. 13, 143–158 (2016).
Wargo, J. A., Reuben, A., Cooper, Z. A., Oh, K. S. & Sullivan, R. J. Immune effects of chemotherapy, radiation, and targeted therapy and opportunities for combination with immunotherapy. Semin. Oncol. 42, 601–616 (2015).
Liu, X. et al. Dual targeting of innate and adaptive checkpoints on tumor cells limits immune evasion. Cell Rep. 24, 2101–2111 (2018).
Maxhimer, J. B. et al. Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. Sci. Transl. Med. 1, 3ra7 (2009).
Soto-Pantoja, D. R. et al. CD47 deficiency confers cell and tissue radioprotection by activation of autophagy. Autophagy 8, 1628–1642 (2012).
Vermeer, D. W. et al. Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer. Int. J. Cancer 133, 120–129 (2013).
Gameiro, S. R. et al. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 5, 403–416 (2014).
Kono, K., Mimura, K. & Kiessling, R. Immunogenic tumor cell death induced by chemoradiotherapy: molecular mechanisms and a clinical translation. Cell Death Dis. 4, e688 (2013).
Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).
Wang, X. et al. Suppression of type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy. Cancer Res. 77, 839–850 (2017).
Deng, L. et al. Sting-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).
Dheilly, E. et al. Selective blockade of the ubiquitous checkpoint receptor CD47 is enabled by dual-targeting bispecific antibodies. Mol. Ther. 25, 523–533 (2017).
Bouguermouh, S. et al. CD47 expression on T cell is a self-control negative regulator of type 1 immune response. J. Immunol. 180, 8073–8082 (2008).
Li, Z. et al. Interactions of thrombospondins with α4β1 integrin and CD47 differentially modulate T cell behavior. J. Cell Biol. 157, 509–519 (2002).
Johnson, L. D. S. et al. Targeting CD47 in Sezary syndrome with SIRPαFc. Blood Adv. 3, 1145–1153 (2019).
Haney, M. S. et al. Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens. Nat. Genet. 50, 1716–1727 (2018).
Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015).
Tang, C., Jiang, W. & Yap, T. A. Efficacy and toxic effects of cancer immunotherapy combinations—a double-edged sword. JAMA Oncol. 4, 1116–1117 (2018).
de Back, D. Z., Kostova, E. B., van Kraaij, M., van den Berg, T. K. & van Bruggen, R. Of macrophages and red blood cells; a complex love story. Front. Physiol. 5, 9 (2014).
Hutter, G. et al. Microglia are effector cells of CD47–SIRPα antiphagocytic axis disruption against glioblastoma. Proc. Natl Acad. Sci. USA 116, 997–1006 (2019).
Lehrman, E. K. et al. CD47 protects synapses from excess microglia-mediated pruning during development. Neuron 100, 120–134. e6. (2018).
Lindberg, F. P., Gresham, H. D., Schwarz, E. & Brown, E. J. Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding. J. Cell Biol. 123, 485–496 (1993).
Lindberg, F. P. et al. Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 274, 795–798 (1996).
Wang, X. Q. & Frazier, W. A. The thrombospondin receptor CD47 (IAP) modulates and associates with α2β1 integrin in vascular smooth muscle cells. Mol. Biol. Cell 9, 865–874 (1998).
Rogers, N. M., Sharifi-Sanjani, M., Csanyi, G., Pagano, P. J. & Isenberg, J. S. Thrombospondin-1 and CD47 regulation of cardiac, pulmonary and vascular responses in health and disease. Matrix Biol. 37, 92–101 (2014).
Isenberg, J. S., Roberts, D. D. & Frazier, W. A. CD47: a new target in cardiovascular therapy. Arterioscler. Thromb. Vasc. Biol. 28, 615–621 (2008).
Coleman, J. W. Nitric oxide in immunity and inflammation. Int. Immunopharmacol. 1, 1397–1406 (2001).
Ticchioni, M. et al. Integrin-associated protein (CD47) is a comitogenic molecule on CD3-activated human T cells. J. Immunol. 158, 677–684 (1997).
Reinhold, M. I., Lindberg, F. P., Kersh, G. J., Allen, P. M. & Brown, E. J. Costimulation of T cell activation by integrin-associated protein (CD47) is an adhesion-dependent, CD28-independent signaling pathway. J. Exp. Med. 185, 1–11 (1997).
Stefanidakis, M., Newton, G., Lee, W. Y., Parkos, C. A. & Luscinskas, F. W. Endothelial CD47 interaction with SIRPγ is required for human T-cell transendothelial migration under shear flow conditions in vitro. Blood 112, 1280–1289 (2008).
Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).
Lester, S. N. & Li, K. Toll-like receptors in antiviral innate immunity. J. Mol. Biol. 426, 1246–1264 (2014).
Hennecke, J. & Wiley, D. C. T cell receptor–MHC interactions up close. Cell 104, 1–4 (2001).
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.
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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- 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.
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.
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.
Cytoplasmic vesicular bodies formed by the fusion of a phagosome with a lysosome during the phagocytosis process.
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.
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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