• Madheswaran Suresh Department of Biotechnology, Dr.M.G.R. Educational and Research Institute (University), Maduravoyal, Chennai 600095. Tamil Nadu, India
  • Malarvizhi Gurusamy Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju, South Korea
  • Natarajan Sudhakar Department of Biotechnology, Dr.M.G.R. Educational and Research Institute (University), Maduravoyal, Chennai 600095. Tamil Nadu, India


Immune surveillance is a mechanism where cells and tissues are watched constantly by ever alerted immune system. Most incipient cancer cells are recognized and eliminated by the immune surveillance mechanism, but still tumors have the ability to evade immune surveillance and immunological killing. One greater arm that tumor use to evade immune surveillance, is by expressing anti-phagocytic signal (CD47). Here we present a provocative hypothesis where cancer cells are removed alive by phagocytic cell (DC). That in turn will elicit effective and higher immunogenic condition. All this could be possible by addition pro-phagocytic signal (PtdSer) over cancer cell surface (Breast Cancer), that mask the presence of anti-phagocytic signal (CD47). In other words, adding eat me signal (PtdSer) over the breast cancer cell surface that mask the presence of don’t eat me signal or anti-phagocytic signal present in breast cancer cell surface. This could be possible by using bi-specific antibody, conjugated to PEG-modified liposomes, which carry (PtdSer) pro-phagocytic signal (or) eat me signal, which target both CD47 and EGFRVIII on breast carcinoma. The simultaneous masking of anti-phagocytic signal, and adding of pro–phagocytic signal over cancer cell, will enhance the phagocytic clearance of live tumor cell and elicit immunological killing.

Keywords: Phagocytosis, CD47, EGFRVIII, Phagocytic cells, PtdSer, Immunological killing


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1. Jaiswal S, Chao MP, Majeti R, Weissman IL. Macrophages as mediators of tumor immunosurveillance. Trends Immunol 2010;31:212-9.
2. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 2009;138:271–85.
3. Sarfati M, Fortin G, Raymond M, Susin S. CD47 in the immune response: role of thrombospondin and SIRP-alpha reverse signaling. Curr Drug Targets 2008;9:842-50.
4. Liu Y, Merlin D, Burst SL, Pochet M, Madara JL, Parkos CA. The role of CD47 in neutrophil transmigration. Increased rate of migration correlates with increased cell surface expression of CD47. J Biol Chem 2001;276:40156-66.
5. Miyashita M, Ohnishi H, Okazawa H, Tomonaga H, Hayashi A, Fujimoto T, et al. Promotion of neurite and filopodium formation by CD47:roles of integrins, Rac, and Cdc42. Mol Biol Cell 2004;15:3950-63.
6. Jiang P, Lagenaur CF, Narayanan V. Integrin-associated protein is a ligand for the P84 neural adhesion molecule. J Biol Chem 1999;274:559-62.
7. Brown EJ, Frazier WA. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol 2001;11:130-5.
8. Oldenborg PA, Gresham HD, Lindberg FP. CD47-signal regulatory protein alpha (SIRP alpha) regulates Fc gamma and complement receptor-mediated phagocytosis. J Exp Med 2001;193:855-62.
9. Blazar BR, Lindberg FP, Ingulli E, Mortari AP, Oldenborg PA, Lizuka K, et al. CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counter receptors is required to prevent the clearance of donor lymphohematopoietic cells. J Exp Med 2001;194:541-9.
10. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138:286-99.
11. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-hodgkin lymphoma. Cell 2010;142:699-13.
12. Rendtlew Danielsen JM, Knudsen LM, Dahl IM, Lodahl M, Rasmussen T. Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myelomas. Br J Haematol 2007;138:756-60.
13. Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A 2009;106:14016-21.
14. Chao MP, Tang C, Pachynski RK, Chin R, Majeti R, Weissman IL. Extranodal dissemination of non-hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood 2011;118:4890-901.
15. Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, et al. Calreticulin is the dominant prophagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2010;2:63r-a94.
16. Mapara MY, Sykes M. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. Clin Oncol 2004;22:1136-51.
17. Chen Q, Daniel V, Maher DW, Hersey P. Production of IL-10 by melanoma cells: Examination of its role in immunosuppression mediated by melanoma. Int J Cancer 1994;56:755-60.
18. Tada T, Ohzeki S, Utsumi K, Takiuchi H, Muramatsu M, Li XF, et al. Transforming growth factor-beta-induced inhibition of T cell function: susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosuppression in the tumor-bearing state. J Immunol 1991;146:1077-82.
19. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001;7:1118-22.
20. Strand S, Hofmann WJ, Hug H, Muller M, Otto G, Strand D, et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells-A mechanism of immune evasion? Nat Med 1996;2:1361-6.
21. Ge H, Gong X, Tang CK. Evidence of high incidence of EGFRvIII expression and coexpression with EGFR in human invasive breast cancer by laser capture microdissection and immunohistochemical analysis. Int J Cancer 2002;98:357–61.
22. Ohshima K, Nakashima M, Sonoda K, Kikuchi M, Watanabe T. Expression of RCAS1 and FasL in human trophoblasts and uterine glands during pregnancy: the possible role in immune privilege. Clin Exp Immunol 2001;123:481-6.
23. Nakashima M, Sonoda K, Watanabe T. Inhibition of cell growth and induction of apoptotic cell death by the human tumor-associated antigen RCAS1. Nat Med 1999;5:938-42.
24. Mizoguchi H, O’Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 1992;258:1795-8.
25. Finke JH, Zea AH, Stanley J, Longo DL, Mizoguchi H, Tubbs RR, et al. Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 1993;53:5613-6.
26. Ochsenbein AF, Klenerman P, Karrer U, Ludewig B, Pericin M, Hengartner H, et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci USA 1999;96:2233-8.
27. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002;169:2756-61.
28. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, et al. Regulatory CD4(+) CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 2001;61:4766-72.
29. Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, et al. Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 2002;168:4272-6.
30. Barclay AN, Brown MH. The SIRP family of receptors and immune regulation. Nat Rev Immunol 2006;6:457–64.
31. Parkos CA, Colgan SP, Liang TW, Nusrat A, Bacarra AE, Cames DK, et al. CD47 mediates post-adhesive events required for neutrophil migration across polarized intestinal epithelia. J Cell Biol 1996;132:437-50.
32. 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 1990;111: 2785-94.
33. Tsai RK, Discher DE. Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J Cell Biol 2008;180:989-1003.
34. Murata T, Ohnishi H, Okazawa H, Murata Y, Kusakari S, Hayashi Y, et al. CD47 promotes neuronal development through Src-and FRG/Vav2-mediated activation of Rac and Cdc42. J Neurosci 2006;26:12397-407.
35. Uluckan O, Becker SN, Deng H, Zou W, Prior JL, Piwnica-Worms D, et al. CD47 regulates bone mass and tumor metastasis to bone. Cancer Res 2009;69:3196-204.
36. Reinhold MI, Lindberg FP, Plas D, Reynolds S, Peters MG, Brown EJ. In vivo expression of alternatively spliced forms of integrin-associated protein (CD47). J Cell Sci 1995;108:3419-25.
37. Tsenga D, Jens-Peter V, Stephen BW, Humberto CT, John WF, Nathaniel BF, et al. Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci 2013;110:11103-8.
38. Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, et al. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science 2013;341:88-91.
39. Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP. et al. Role of CD47 as a marker of self on red blood cells. Science 2000;288:2051-4.
40. Kershaw MH, Smyth MJ. Making macrophages eat cancer. Science 2013;341:41-2.
41. Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, et al. Epidermal growth factor ligand-independent, unregulated, the cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ 1995;6:1251-9.
42. Huang HS, Nagane M, Klingbeil CK, Lin H, Nishikawa R, Ji XD, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem 1997;272:2927-35.
43. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci 1992;89:2965-9.
44. Chao MP, Weissman IL, Majeti R. The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 2012;24:225-32.
45. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 2005;123:321-34.
46. Borisenko GG, Matsura T, Liu SX, Tyurin VA, Jianfei J, Serinkan FB, et al. Macrophage recognition of externalized phosphatidylserine and phagocytosis of apoptotic jurkat cells existence of a threshold. Arch Biochem Biophys 2003;413:41-52.
47. Fadok VA, de Cathelineau A, Daleke DL, Henson PM, Bratton DL. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. J Biol Chem 2001;276:1071-7.
48. Choi BD, Kuan CT, Cai M, Archer GE, Mitchell DA, Gedeon PC, et al. Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma. Proc Natl Acad Sci 2013;110:270-5.
49. Yu H, Gong X, Luo X, Han W, Hong G, Singh B, et al. Co-expression of EGFRvIII with ErbB-2 enhances tumorigenesis: EGFRvIII mediated constitutively activated and sustained signaling pathways, whereas EGF-induced a transient effect on EGFR-mediated signaling pathways. Cancer Biol Ther 2008;7:1818–28.
50. Grandal MV, Zandi R, Pedersen MW, Willumsen BM, Vandeurs B, Poulsen HS, et al. EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes. Carcinogenesis 2007;28:1408-17.
51. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 2008;18:54-61.
52. Chiu GN, Bally MB, Mayer LD. Targeting of antibody conjugated, phosphatidylserine-containing liposomes to vascular cell adhesion molecule 1 for controlled thrombogenesis. Biochim Biophys Acta 2003;1613:115-21.
53. Chiu GN, Bally MB, Mayer LD. Effects of phosphatidylserine on membrane incorporation and surface protection properties of exchangeable poly(ethylene glycol)-conjugated lipids. Biochim Biophys Acta 2002;1560:37-50.
54. Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 2007;450:430-4.
55. He M, Kubo H, Morimoto K, Fujino N, Suzuki T, Takahasi T, et al. Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Rep 2011;12:358-64.
56. Gumienny TL, Brugnera E, Tosello-Trampont AC, Kinchen JM, Haney LB, Nishiwaki K, et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 2001;107:27-41.
57. Miki H, Suetsugu S, Takenawa T. WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. EMBO J 1998;17:6932-41.
58. Castellano F, Montcourrier P, Chavrier P. Membrane recruitment of Rac1 triggers phagocytosis. J Cell Sci 2000;113:2955-61.
59. Nagata S, Hanayama R, Kawane K. Autoimmunity and the clearance of dead cells. Cell 2010;140:619-30.
60. Kinchen JM, Ravichandran KS. Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. Nature 2010;464:778-82.
61. Schroit AJ, Madsen JW, Tanaka Y. In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J Biol Chem 1985;260:5131-8.
62. Wagner BJ, Lindau D, Ripper D, Stierhof YD, Glatzle J, Witte M, et al. Phagocytosis of dying tumor cells by human peritoneal mesothelial cells. J Cell Sci 2011;124:1644-54.
63. Alan A. How to eat something bigger than your head. Cell 2002;110:5-8.
64. Segawa K, Suzuki J, Nagata S. Constitutive exposure of phosphatidylserine on viable cells. Proc Natl Acad Sci 2011;108:19246-51.
65. Van den Eijnde SM, Van den Hoff MJ, Reutelingsperger CP, Van Heerde WL, Henfling ME, Vermeij Keers C, et al. Transient expression of phosphatidylserine at cell–cell contact areas is required for myotube formation. J Cell Sci 2001;114:3631-42.
66. Helming L, Gordon S. Molecular mediators of macrophage fusion. Trends Cell Biol 2009;19:514-22.
67. Pardoll DM. Cancer vaccines. Nat Med 1998;4 Suppl 5:525-31.
68. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-52.
69. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature 2007;449:419-26.
70. Anderson HA, Englert R, Gursel I, Shacter E. Oxidative stress inhibits the phagocytosis of apoptotic cells that have externalized phosphatidylserine. Cell Death Differ 2002;9:616-25.
71. Shacter E, Williams JA, Hinson RM, Sentürker S, Lee YJ. Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis. Blood 2000;96:307-13.
72. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998;392:86-9.
73. Maranon C, Desoutter JF, Hoeffel G, Cohen W, Hanau D, Hosmalin A. Dendritic cells cross-present HIV antigens from live as well as apoptotic infected CD4+T lymphocytes. Proc Natl Acad Sci USA 2004;101:6092-7.
74. Lui G, Manches O, Angel J, Molens JP, Chaperot L, Plumas J. Plasmacytoid Dendritic cells capture and cross-present viral antigens from Influenza virus exposed cells. PLoS One 2009;4:e7111.
75. Dhodapkar MV, Krasovsky J, Olson K. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumour-specific cytolytic responses to autologous, tumor-loaded dendritic cells. Proc Natl Acad Sci USA 2002;99:13009-13.
76. Labarriere N, Bretaudeau L, Gervois N, Bodinier M, Bougras G, Diez E, et al. Apoptotic body-loaded dendritic cells efficiently cross-prime cytotoxic T lymphocytes specific for NA17-A antigen but not for Melan-A/MART-1 antigen. Int J Cancer 2002;101:280-6.
77. Tobiasova Z, Pospisilova D, Miller AM, Minarik I, Sochorova K, Spisek R, et al. In vitro assessment of dendritic cells pulsed with apoptotic tumour cells as a vaccine for ovarian cancer patients. Clin Immunol 2007;122:18-27.
78. Matheoud D, Perié L, Hoeffel G, Vimeux L, Parent I, Maranon C, et al. Cross-presentation by dendritic cells from live cells induces protective immune responses in vivo. Blood 2010;115:4412-20.
79. Ronchetti A, Rovere P, Iezzi G, Galati G, Heltai S, Protti MP, et al. Immunogenicity of apoptotic cells in vivo: the role of antigen load, antigen-presenting cells, and cytokines. J Immunol 1999;163:130-6.
80. Harshyne LA, Zimmer MI, Watkins SC, Baratt-Boyes SM. A role for class A scavenger receptor in dendritic cell nibbling from live cells. J Immunol 2003;170:2302-9.
81. Gardai SJ, Bratton DL, Ogden CA, Henson PM. Recognition ligands on apoptotic cells: a perspective. J Leukoc Biol 2006; 79:896-903.
82. Inge TH, Hoover SK, Susskind BM, Barrett SK, Bear HD. Inhibition of tumor-specific cytotoxic T-lymphocyte responses by transforming growth factor beta 1. Cancer Res 1992;52:1386-92.
83. Okazawa H, Motegi S, Ohyama N, Ohnishi H, Tomizawa T, Kaneko Y, et al. Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system. J Immunol 2005; 174:2302-9.
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How to Cite
Suresh, M., M. Gurusamy, and N. Sudhakar. “MASKING ANTI-PHAGOCYTIC SIGNAL OF TUMOR BY PRO-PHAGOCYTIC SIGNAL-A KEY TO IMMUREMENT OF CANCER CELL”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 8, no. 9, Sept. 2016, pp. 323-8, doi:10.22159/ijpps.2016v8i9.12990.