Immune Response in Melanoma: A Basis to Understand the Role of Immunotherapy with Immune Checkpoint Inhibitors

  • Eugénia Matos Pires Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central
  • Cecília Moura Instituto Português de Oncologia de Lisboa Francisco Gentil
Keywords: Immunologic Surveillance, Immunotherapy, Melanoma/immunology, Melanoma/therapy, Programmed Cell Death 1 Receptor


The knowledge of the pathophysiology of tumour progression is crucial to understand the therapeutic targets in order to control the disease. The mechanisms used by the immune system to affect cancer development and progression has been a challenging question in immunology. It is now postulated that immunology plays a dual role in this process: it protects against tumour growth, destroying “aberrant” tumour cells, but may also promote tumour progression by selecting tumour cells that are able to escape the immune response and survive in an immunocompetent host. These findings gave rise to the concept of “cancer immunoediting”, which explains the influence of the immune system on tumour progression. Several observations like immunosuppression as a risk factor for melanoma, the possibility of partial or complete regression of primary tumour and development of vitiligo, have suggested that melanoma is an immunogenic tumour but a successful tumour evolution can occur in the light of the “immunoediting” concept. Immune checkpoints, cytotoxic T lymphocyte antigen (CTLA)-4 and programmed cell death (PD-1), were recognized to have important roles in regulating T cell responses during tumour development and were proven to be effective targets in treating advanced melanoma. This article will briefly review the process of tumour evolution and its interaction with the immune system as well as the mechanism of action of the immune checkpoint inhibitors to understand better the new targeted immunotherapies for advanced melanoma, that will be further discussed.


Download data is not yet available.


– Burnet M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J. 1957; 1: 841–847.

- Stutman O. Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science. 1974 ;183(4124):534-6.

- Stutman O. Immunodepression and malignancy. Adv Cancer Res. 1975; 22: 261-422.

Old lJ, Boyse EA. Immunonology of experimental tumors. Annu Rev Med. 1964; 15:167-86.

- Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 2003; 21: 807-39.

- Balkwill F, Mantovani A. Cancer and inflammation: implications for pharmacology and therapeutics. Clin Pharmacol Ther. 2010 ; 87: 401-6.

- Vendramini-Costa DB, Carvalho JE. Molecular link mechanisms between inflammation and cancer. Curr Pharm Des. 2012;18(26):3831-52.

- Dighe AS, Richards E, Old LJ, Schreiber RD. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity. 1994 ;1(6):447-56.

- Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011; 29: 235-71.

- Silverberg MJ, Chao C, Leyden WA, Xu L, Horberg MA, Klein D et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev. 2011; 20: 2551-9

- Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002; 3: 991-8.

- Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331: 1565-70.

- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-74.

- Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015; 35: Suppl:S185-S198

- Yuan J, Page DB, Ku GY, Li Y, Mu Z, Ariyan C, et al. Correlation of clinical and immunological data in a metastatic melanoma patient with heterogeneous tumor responses to ipilimumab therapy. Cancer Immun. 2010; 10: 1.

- Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711-23.

- Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366: 2455-65.

- Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 ; 366: 2443-54.

- Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr Opin Immunol. 2014; 27: 16-25.

- Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331: 1565-70.

- Atsumi T, Singh R, Sabharwal L, Bando H, Meng J, Arima Y et al. Inflammation amplifier, a new paradigm in cancer biology. Cancer Res. 2014; 74: 8-14.

- Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007; 450: 903-7.

- Khong HT, Restifo NP. Natural selection of tumor variants in the generation of "tumor escape" phenotypes. Nat Immunol. 2002; 3: 999-1005.

- Chikuma S. Basics of PD-1 in self-tolerance, infection, and cancer immunity. Int J Clin Oncol. 2016 Jun;21(3):448-55

- Kee D, McArthur G. Immunotherapy of melanoma. Eur J Surg Oncol. 2017; 43: 594-603

- Sanlorenzo M, Vujic I, Posch C, Dajee A, Yen A, Kim S, et al. Melanoma immunotherapy. Cancer Biol Ther. 2014; 15: 665-74.

- Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987; 328: 267-70.

- Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011; 11: 852-63.

– Chikuma S. CTLA-4, an Essential Immune-Checkpoint for T-Cell Activation. Curr Top Microbiol Immunol. 2017. doi: 10.1007/82_2017_61. [Epub ahead of print]

- Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995; 182: 459-65.

- Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994; 1: 405-13.

- Wells AD, Walsh MC, Bluestone JA, Turka LA. Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy. J Clin Invest. 2001; 108: 895-903.

- Schwartz RH. T cell anergy. Annu Rev Immunol. 2003; 21: 305-34.

- Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 2009; 206:1717–1725.

- Chambers CA, Cado D, Truong T, Allison JP. Thymocyte development is normal in CTLA-4-deficient mice. Proc Natl Acad Sci U S A. 1997; 94: 9296-301.

- Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev. 2008; 223: 143-55.

- Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996; 271: 1734-6.

- Shrikant P, Khoruts A, Mescher MF. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity. 1999; 11: 483-93.

- Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007; 19: 813–824.

- Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366: 2455-65.

- Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N, et al. Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4 CD8 ) thymocytes. Int Immunol. 1996; 8: 773-80.

- 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. 1992;11:3887–3895.

- Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12: 252-64.

- Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009; 114: 1537–1544.

- Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature Med. 2002; 8:793–800.

- Tsirigotis P, Savani BN, Nagler A. Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies. Ann Med. 2016; 48: 428-439.

- Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014; 515: 568-71.

- Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012; 4:127ra37.

- Frydenlund N, Mahalingam M. PD-L1 and immune escape: insights from melanoma and other lineage-unrelated malignancies. Hum Pathol. 2017; 66: 13-33.

How to Cite
Matos Pires, E., & Moura, C. (2018). Immune Response in Melanoma: A Basis to Understand the Role of Immunotherapy with Immune Checkpoint Inhibitors. Journal of the Portuguese Society of Dermatology and Venereology, 76(1), 47-52.
Review Articles