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Current Molecular Medicine

Author(s): Shaho Ghahremani Dehbokri, Nazila Alizadeh, Alireza Isazadeh, Amir Baghbanzadeh, Soheil Abbaspour-Ravasjani, Khalil Hajiasgharzadeh and Behzad Baradaran*

DOI: 10.2174/1566524022666220610094716

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CTLA-4: As an Immunosuppressive Immune Checkpoint in Breast Cancer

Page: [521 - 526] Pages: 6

  • * (Excluding Mailing and Handling)

Abstract

Breast cancer (BC) is one of the prevalent diseases and causes of death in women, and its incidence rate is increasing in numerous developed and developing countries. The common approach to BC therapy is surgery, followed by radiation therapy or chemotherapy, which doesn't lead to acceptable outcomes in many patients. Therefore, developing innovative strategies for treating BC is essential for the most effective therapy. The immunotherapy of BC is a promising and attractive strategy that can increase the immune system's capacity to recognize and kill the tumor cells, inhibit the recurrence of the tumors, and develop new metastatic sites. The blockade of immune checkpoints is the most attractive and promising strategy for cancer immunotherapy. The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a cellsurface glycoprotein expressed by stimulated T cells and has pivotal roles in cell cycle modulation, cytokine generation, and regulation of T cell proliferation. Currently, anti- CTLA-4 agents such as monoclonal antibodies (Ipilimumab and tremelimumab) are broadly applied as therapeutic agents in clinical studies of different cancers. The anti- CTLA-4 antibodies, alone or combined with other therapeutic agents, remarkably increased the tumor-suppressive effects of the immune system and improved the prognosis of cancer. The immune checkpoint inhibitors may represent promising options for BC treatment as in monotherapy or in combination with other conventional treatments. In this review, we discuss the role of CTLA-4 and its therapeutic potential by inhibitors of immune checkpoints in BC therapeutics.

Keywords: Breast cancer, CTLA-4, immunotherapy, monoclonal antibody, immune, immunosuppressive, immune checkpoint.

[1]
Rezaeian M, Sharifirad G, Mostafavi F, Moodi M, Abbasi MH. The effects of breast cancer educational intervention on knowledge and health beliefs of women 40 years and older, Isfahan, Iran. J Educ Health Promot 2014; 3: 43.
[PMID: 25013836]
[2]
Rock CL, Flatt SW, Thomson CA, et al. Effects of a high-fiber, low-fat diet intervention on serum concentrations of reproductive steroid hormones in women with a history of breast cancer. J Clin Oncol 2004; 22(12): 2379-87.
[http://dx.doi.org/10.1200/JCO.2004.09.025] [PMID: 15197199]
[3]
Fathi Maroufi N, Aghayi E, Garshasbi H, et al. Association of rs1946518 C/A polymorphism in promoter region of interleukin 18 gene and breast cancer risk in Iranian women: A case-control study. Iran J Allergy Asthma Immunol 2019; 18(6): 671-8.
[PMID: 32245311]
[4]
DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin 2014; 64(1): 52-62.
[http://dx.doi.org/10.3322/caac.21203] [PMID: 24114568]
[5]
Maroufi NF, Vahedian V, Akbarzadeh M, et al. The apatinib inhibits breast cancer cell line MDA-MB-231 in vitro by inducing apoptosis, cell cycle arrest, and regulating nuclear factor-κB (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways. Breast Cancer 2020; 27(4): 613-20.
[http://dx.doi.org/10.1007/s12282-020-01055-6] [PMID: 32026267]
[6]
Maroufi NF, Rashidi M, Vahedian V, et al. Effect of Apatinib plus melatonin on vasculogenic mimicry formation by cancer stem cells from breast cancer cell line. Breast Cancer 2021; 1-4.
[PMID: 34725795]
[7]
Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10(1): 29-37.
[http://dx.doi.org/10.1038/ni.1679] [PMID: 19043418]
[8]
Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation. Immunity 2016; 44(5): 989-1004.
[http://dx.doi.org/10.1016/j.immuni.2016.05.001] [PMID: 27192565]
[9]
Isazadeh A, Hajazimian S, Garshasbi H, et al. Resistance mechanisms to immune checkpoints blockade by monoclonal antibody drugs in cancer immunotherapy: Focus on myeloma. J Cell Physiol 2021; 236(2): 791-805.
[http://dx.doi.org/10.1002/jcp.29905] [PMID: 32592235]
[10]
Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature 1987; 328(6127): 267-70.
[http://dx.doi.org/10.1038/328267a0] [PMID: 3496540]
[11]
Lafage-Pochitaloff M, Costello R, Couez D, et al. Human CD28 and CTLA-4 Ig superfamily genes are located on chromosome 2 at bands q33-q34. Immunogenetics 1990; 31(3): 198-201.
[http://dx.doi.org/10.1007/BF00211556] [PMID: 2156778]
[12]
Howard TA, Rochelle JM, Seldin MF. CD28 and CTLA-4, two related members of the Ig supergene family, are tightly linked on proximal mouse chromosome 1. Immunogenetics 1991; 33(1): 74-6.
[http://dx.doi.org/10.1007/BF00211698] [PMID: 1671668]
[13]
Dariavach P, Mattéi MG, Golstein P, Lefranc MP. Human Ig superfamily CTLA-4 gene: Chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol 1988; 18(12): 1901-5.
[http://dx.doi.org/10.1002/eji.1830181206] [PMID: 3220103]
[14]
Lee KM, Chuang E, Griffin M, et al. Molecular basis of T cell inactivation by CTLA-4. Science 1998; 282(5397): 2263-6.
[http://dx.doi.org/10.1126/science.282.5397.2263] [PMID: 9856951]
[15]
Schneider H, Prasad KV, Shoelson SE, Rudd CE. CTLA-4 binding to the lipid kinase phosphatidylinositol 3-kinase in T cells. J Exp Med 1995; 181(1): 351-5.
[http://dx.doi.org/10.1084/jem.181.1.351] [PMID: 7807015]
[16]
Laurent S, Carrega P, Saverino D, et al. CTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions. Hum Immunol 2010; 71(10): 934-41.
[http://dx.doi.org/10.1016/j.humimm.2010.07.007] [PMID: 20650297]
[17]
Contardi E, Palmisano GL, Tazzari PL, et al. CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction. Int J Cancer 2005; 117(4): 538-50.
[http://dx.doi.org/10.1002/ijc.21155] [PMID: 15912538]
[18]
Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007; 445(7129): 771-5.
[http://dx.doi.org/10.1038/nature05543] [PMID: 17220874]
[19]
Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994; 1(9): 793-801.
[http://dx.doi.org/10.1016/S1074-7613(94)80021-9] [PMID: 7534620]
[20]
Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1(5): 405-13.
[http://dx.doi.org/10.1016/1074-7613(94)90071-X] [PMID: 7882171]
[21]
Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991; 174(3): 561-9.
[http://dx.doi.org/10.1084/jem.174.3.561] [PMID: 1714933]
[22]
Schwartz RH. Costimulation of T lymphocytes: The role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 1992; 71(7): 1065-8.
[http://dx.doi.org/10.1016/S0092-8674(05)80055-8] [PMID: 1335362]
[23]
Egen JG, Kuhns MS, Allison JP. CTLA-4: New insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002; 3(7): 611-8.
[http://dx.doi.org/10.1038/ni0702-611] [PMID: 12087419]
[24]
Boasso A, Herbeuval JP, Hardy AW, Winkler C, Shearer GM. Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4+ T cells. Blood 2005; 105(4): 1574-81.
[http://dx.doi.org/10.1182/blood-2004-06-2089] [PMID: 15466932]
[25]
Grohmann U, Orabona C, Fallarino F, et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 2002; 3(11): 1097-101.
[http://dx.doi.org/10.1038/ni846] [PMID: 12368911]
[26]
Li D, Gál I, Vermes C, et al. Cutting edge: Cbl-b: One of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation. J Immunol 2004; 173(12): 7135-9.
[http://dx.doi.org/10.4049/jimmunol.173.12.7135] [PMID: 15585834]
[27]
Schneider H, Smith X, Liu H, Bismuth G, Rudd CE. CTLA-4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization. Eur J Immunol 2008; 38(1): 40-7.
[http://dx.doi.org/10.1002/eji.200737423] [PMID: 18095376]
[28]
Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 2009; 229(1): 12-26.
[http://dx.doi.org/10.1111/j.1600-065X.2009.00770.x] [PMID: 19426212]
[29]
Chuang E, Fisher TS, Morgan RW, et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 2000; 13(3): 313-22.
[http://dx.doi.org/10.1016/S1074-7613(00)00031-5] [PMID: 11021529]
[30]
Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25(21): 9543-53.
[http://dx.doi.org/10.1128/MCB.25.21.9543-9553.2005] [PMID: 16227604]
[31]
Kubsch S, Graulich E, Knop J, Steinbrink K. Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: Association with IL-2- and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1. Eur J Immunol 2003; 33(7): 1988-97.
[http://dx.doi.org/10.1002/eji.200323600] [PMID: 12884865]
[32]
Blank CU. The perspective of immunotherapy: New molecules and new mechanisms of action in immune modulation. Curr Opin Oncol 2014; 26(2): 204-14.
[http://dx.doi.org/10.1097/CCO.0000000000000054] [PMID: 24424272]
[33]
Yu H, Yang J, Jiao S, Li Y, Zhang W, Wang J. Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: Implications for prognosis. Cancer Immunol Immunother 2015; 64(7): 853-60.
[http://dx.doi.org/10.1007/s00262-015-1696-2] [PMID: 25893809]
[34]
Jaberipour M, Habibagahi M, Hosseini A, Habibabad SR, Talei A, Ghaderi A. Increased CTLA-4 and FOXP3 transcripts in peripheral blood mononuclear cells of patients with breast cancer. Pathol Oncol Res 2010; 16(4): 547-51.
[http://dx.doi.org/10.1007/s12253-010-9256-8] [PMID: 20306312]
[35]
Erfani N, Razmkhah M, Ghaderi A. Circulating soluble CTLA4 (sCTLA4) is elevated in patients with breast cancer. Cancer Invest 2010; 28(8): 828-32.
[http://dx.doi.org/10.3109/07357901003630934] [PMID: 20482250]
[36]
Blank CU, Haanen JB, Ribas A, Schumacher TN. Cancer immunology. The “cancer immunogram”. Science 2016; 352(6286): 658-60.
[http://dx.doi.org/10.1126/science.aaf2834] [PMID: 27151852]
[37]
Poust J. Targeting metastatic melanoma. Am J Health Syst Pharm 2008; 65(24) (Suppl. 9): S9-S15.
[http://dx.doi.org/10.2146/ajhp080461] [PMID: 19052265]
[38]
Kim DW, Trinh VA, Hwu WJ. Ipilimumab in the treatment of advanced melanoma - a clinical update. Expert Opin Biol Ther 2014; 14(11): 1709-18.
[http://dx.doi.org/10.1517/14712598.2014.963053] [PMID: 25250971]
[39]
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711-23.
[http://dx.doi.org/10.1056/NEJMoa1003466] [PMID: 20525992]
[40]
Su M, Huang CX, Dai AP. Immune checkpoint inhibitors: Therapeutic tools for breast cancer. Asian Pac J Cancer Prev 2016; 17(3): 905-10.
[http://dx.doi.org/10.7314/APJCP.2016.17.3.905] [PMID: 27039716]
[41]
Zhong L, Zhao Y, Zhang K, Li X, Cui R, Yang W. Recent advances of immune checkpoint in breast cancer. Biomed Res 2017; 28(16)
[42]
Bristol-Myers Squibb. Study of MDX-010 in stage IV breast cancer. 2012.
[43]
Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009; 15(17): 5379-88.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0265] [PMID: 19706802]
[44]
Ribas A. Clinical development of the anti-CTLA-4 antibody tremelimumab. Semin Oncol 2010; 37(5): 450-4.
[http://dx.doi.org/10.1053/j.seminoncol.2010.09.010] [PMID: 21074059]
[45]
Mohit E, Hashemi A, Allahyari M. Breast cancer immunotherapy: Monoclonal antibodies and peptide-based vaccines. Expert Rev Clin Immunol 2014; 10(7): 927-61.
[http://dx.doi.org/10.1586/1744666X.2014.916211] [PMID: 24867051]
[46]
Weber J, Hamid O, Amin A, et al. Randomized phase I pharmacokinetic study of ipilimumab with or without one of two different chemotherapy regimens in patients with untreated advanced melanoma. Cancer Immun 2013; 13(2): 7.
[PMID: 23833564]
[47]
Arriola E, Wheater M, Galea I, et al. Outcome and biomarker analysis from a multicenter phase 2 study of ipilimumab in combination with carboplatin and etoposide as first-line therapy for extensive-stage SCLC. J Thorac Oncol 2016; 11(9): 1511-21.
[http://dx.doi.org/10.1016/j.jtho.2016.05.028] [PMID: 27296105]
[48]
Tang C, Welsh JW, de Groot P, et al. Ipilimumab with stereotactic ablative radiation therapy: Phase I results and immunologic correlates from peripheral T cells. Clin Cancer Res 2017; 23(6): 1388-96.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1432] [PMID: 27649551]
[49]
Engeland CE, Grossardt C, Veinalde R, et al. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol Ther 2014; 22(11): 1949-59.
[http://dx.doi.org/10.1038/mt.2014.160] [PMID: 25156126]
[50]
Jure-Kunkel MN, Masters G, Girit E, Dito G, Lee FY. Antitumor activity of anti- CTLA-4 monoclonal Antibody (mAb) in combination with ixabepilone in preclinical tumor models. J Clin Oncol 2008; 26(15): 3048.
[http://dx.doi.org/10.1200/jco.2008.26.15_suppl.3048]
[51]
Fathi Maroufi N, Gholampour Matin M, Ghanbari N, et al. Influence of single nucleotide polymorphism in IL-27 and IL-33 genes on breast cancer. Br J Biomed Sci 2019; 76(2): 89-91.
[http://dx.doi.org/10.1080/09674845.2018.1545554] [PMID: 30406733]
[52]
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348(6230): 124-8.
[http://dx.doi.org/10.1126/science.aaa1348] [PMID: 25765070]
[53]
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371(23): 2189-99.
[http://dx.doi.org/10.1056/NEJMoa1406498] [PMID: 25409260]
[54]
Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012; 486(7403): 346-52.
[http://dx.doi.org/10.1038/nature10983] [PMID: 22522925]
[55]
Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264): 1084-9.
[http://dx.doi.org/10.1126/science.aac4255] [PMID: 26541606]
[56]
Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350(6264): 1079-84.
[http://dx.doi.org/10.1126/science.aad1329] [PMID: 26541610]