Immune Checkpoint Inhibitors: Therapeutic Tools for Breast Cancer

  • Su, Min (Department of Human Anatomy, Histology and Embryology, Institute of Neuroscience, Changsha Medical University) ;
  • Huang, Chun-Xia (Department of Human Anatomy, Histology and Embryology, Institute of Neuroscience, Changsha Medical University) ;
  • Dai, Ai-Ping (Department of Human Anatomy, Histology and Embryology, Institute of Neuroscience, Changsha Medical University)
  • Published : 2016.04.11


Breast cancer is one of the major threats to female health, and its incidence is rapidly increasing in many countries. Currently, breast cancer is treated with surgery, followed by chemotherapy or radiation therapy, or both. However, a substantial proportion of breast cancer patients might have a risk for local relapse that leads to recurrence of their disease and/or metastatic breast cancer. Therefore searching for new and potential strategies for breast cancer treatment remains necessary. Immunotherapy is an attractive and promising approach that can exploit the ability of the immune system to identify and destroy tumors and thus prevent recurrence and metastatic lesions. The most promising and attractive approach of immunotherapeutic research in cancer is the blockade of immune checkpoints. In this review, we discuss the potential of certain inhibitors of immune checkpoints, such as antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3), in breast cancer therapeutics. Immune checkpoint inhibitors may represent future standards of care for breast cancer as monotherapy or combined with standard therapies.


Supported by : Changsha Medical University


  1. Agarwal G, Ramakant P, Forgach ER, et al (2009). Breast cancer care in developing countries. World J Surg, 33, 2069-76.
  2. Ascierto PA, Marincola FM (2014). What have we learned from cancer immunotherapy in the last 3 years? J Transl Med, 12, 141.
  3. Blackburn GL, Wang KA (2007). Dietary fat reduction and breast cancer outcome:results from the Women’s Intervention Nutrition Study (WINS). Am J Clin Nutr, 86, 878-81.
  4. Blank CU (2014). The perspective of immunotherapy: new molecules and new mechanisms of action in immune modulation. Curr Opin Oncol, 26, 204-14.
  5. Brahmer JR, Tykodi SS, Chow LQ, et al (2012). Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 366, 2455-65.
  6. Brignone C, Gutierrez M, Mefti F, et al (2010). First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med, 8, 71.
  7. Cappello P, Triebel F, Iezzi M, et al (2003). LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice. Cancer Res, 63, 2518-25.
  8. Carreno BM, Bennett F, Chau TA, et al (2000). CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. J Immunol, 165, 1352-6.
  9. Chen L, Flies DB (2013). Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol, 13, 227-42.
  10. Criscitiello C, Curigliano G (2013). Immunotherapeutics for breast cancer. Curr Opin Oncol, 25, 602-8.
  11. Demaria S, Kawashima N, Yang AM, et al (2005). Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res, 11, 728-34.
  12. DeSantis C, Ma J, Bryan L, Jemal A (2014). Breast cancer statistics, 2013. CA Cancer J Clin, 64, 52-62.
  13. Dolan DE, Gupta S (2014). PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control, 21, 231-7.
  14. Ernst B, Anderson KS (2015). Immunotherapy for the treatment of breast cancer. Curr Oncol Rep, 17, 426.
  15. Gandhi MK, Lambley E, Duraiswamy J, et al (2006). Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood, 108, 2280-9.
  16. Gatalica Z, Snyder C, Maney T, et al (2014). Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev, 23, 2965-70.
  17. Ge Y, Xi H, Ju S, Zhang X (2013). Blockade of PD-1/PD-L1 immune checkpoint during DC vaccination induces potent protective immunity against breast cancer in hu-SCID mice. Cancer Lett, 336, 253-9.
  18. Ghochikyan A, Pichugin A, Bagaev A, et al (2014). Targeting TLR-4 with a novel pharmaceutical grade plant derived agonist, Immunomax$^{(R)}$, as a therapeutic strategy for metastatic breast cancer. J Transl Med, 12, 322.
  19. Goldberg MV, Drake CG (2011). LAG-3 in Cancer Immunotherapy. Curr Top Microbiol Immunol, 344, 269-78.
  20. Gursoy AA, Ylmaz F, Nural N, et al (2009). A different approach to breast self-examination education: daughters educating mothers creates positive results in Turkey. Cancer Nurs, 32, 127-34.
  21. Hamid O, Robert C, Daud A, et al (2013). Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med, 369, 134-44.
  22. Hao MZ, Zhou WY, Du XL, et al (2014). Novel anti-melanoma treatment: focus on immunotherapy. Chin J Cancer, 33, 458-65.
  23. Hodi FS, O'Day SJ, McDermott DF, et al (2010). Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 363, 711-23.
  24. Hurwitz AA, Yu TF, Leach DR, Allison JP (1998). CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci U S A, 95, 10067-71.
  25. Ileana E, Champiat S, Soria JC (2013). Immune-checkpoints: the new anti-cancer immunotherapies. Bull Cancer, 100, 601-10.
  26. Intlekofer AM, Thompson CB (2013). At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol, 94, 25-39.
  27. Jago CB, Yates J, Camara NO, Lechler RI, Lombardi G (2004). Differential expression of CTLA-4 among T cell subsets. Clin Exp Immunol, 136, 463-71.
  28. Janakiram M, Abadi YM, Sparano JA, Zang X (2012). T cell coinhibition and immunotherapy in human breast cancer. Discov Med, 14, 229-36.
  29. Jones SC, Gregory P, Nehill C, et al (2010). Australian women's awareness of breast cancer symptoms and responses to potential symptoms. Cancer Causes Control, 21, 945-58.
  30. Karyampudi L, Lamichhane P, Scheid AD, et al (2014). Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. Cancer Res, 74, 2974-85.
  31. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008). PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 26, 677-704.
  32. Kong YC, Wei WZ, Tomer Y (2010). Opportunistic autoimmune disorders: from immunotherapy to immune dysregulation. Ann N Y Acad Sci, 1183, 222-36.
  33. Lesterhuis WJ, Haanen JB, Punt CJ (2011). Cancer immunotherapy--revisited. Nat Rev Drug Discov, 10, 591-600.
  34. Macon-Lemaitre L, Triebel F (2005). The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunol, 115, 170-8.
  35. Murala S, Alli V, Kreisel D, Gelman AE, Krupnick AS (2010). Current status of immunotherapy for the treatment of lung cancer. J Thorac Dis, 2, 237-44.
  36. Pardoll DM (2012). The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 12, 252-64.
  37. Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A (2014). Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol, 153, 145-52.
  38. Perica K, Varela JC, Oelke M, Schneck J (2015). Adoptive T cell immunotherapy for cancer. Rambam Maimonides Med J, 6, 4.
  39. Pilones KA, Kawashima N, Yang AM, et al (2009). Invariant natural killer T cells regulate breast cancer response to radiation and CTLA-4 blockade. Clin Cancer Res, 15, 597-606.
  40. Poust J (2008). Targeting metastatic melanoma. Am J Health Syst Pharm, 65, 9-15.
  41. Qureshi OS, Zheng Y, Nakamura K, et al (2011). Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science, 332, 600-3.
  42. Ramsay DT, Kent JC, Hartmann RA, Hartmann PE (2005). Anatomy of the lactating human breast redefined with ultrasound imaging. J Anat, 206, 525-34.
  43. Reuben JM, Lee BN, Li C, et al (2006). Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer, 106, 2437-44.
  44. Rezaeian M, Sharifirad G, Mostafavi F, Moodi M, Abbasi MH (2014). The effects of breast cancer educational intervention on knowledge and health beliefs of women 40 years and older, Isfahan, Iran. J Educ Health Promot, 3, 43.
  45. Rock CL, Flatt SW, Thomson CA, et al (2004). 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, 22, 2379-87.
  46. Rothschild SI, Thommen DS, Moersig W, Muller P, Zippelius A (2015). Cancer immunology - development of novel anticancer therapies. Swiss Med Wkly, 145, 14066.
  47. Rudd CE, Taylor A, Schneider H (2009). CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev, 229, 12-26.
  48. Saslow D, Hannan J, Osuch J, et al (2004). Clinical breast examination: practical recommendations for optimizing performance and reporting. CA Cancer J Clin, 54, 327-44.
  49. Schlom J (2012). Therapeutic cancer vaccines: current status and moving forward. J Natl Cancer Inst, 104, 599-613.
  50. Selby MJ, Engelhardt JJ, Quigley M, et al (2013). Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res, 1, 32-42.
  51. Sharma P, Wagner K, Wolchok JD, Allison JP (2011). Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer, 11, 805-12.
  52. Shin DS, Ribas A (2015). The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr Opin Immunol, 33, 23-35.
  53. Shore ND (2015). Advances in the understanding of cancer immunotherapy. BJU Int, 116, 321-9.
  54. Stagg J, Allard B (2013). Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects. Ther Adv Med Oncol, 5, 169-81.
  55. Takahashi T, Tagami T, Yamazaki S, et al (2000). Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med, 192, 303-10.
  56. Triebel F (2003). LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination. Trends Immunol, 24, 619-22.
  57. Vonderheide RH, LoRusso PM, Khalil M, et al (2010). Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res, 16, 3485-94.
  58. Wang DH, Guo L, Wu XH (2015). Checkpoint inhibitors in immunotherapy of ovarian cancer. Tumor Biol, 36, 33-9.
  59. Weber JS, Kudchadkar RR, Yu B, et al (2013). Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol, 31, 4311-8.
  60. Wright SE (2012). Immunotherapy of breast cancer. Expert Opin Biol Ther, 12, 479-90.
  61. Yano H, Thakur A, Tomaszewski EN, et al (2014). Ipilimumab augments antitumor activity of bispecific antibody-armed T cells. J Transl Med, 12, 191.

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