Melanoma Pathophysiology

Melanocytes are found in the basal layer of the epidermis and are responsible for producing melanin.1 The transformation of melanocytes into melanoma cells encompasses clonal successions and acquisition of deleterious genomic alterations.2 After the vertical phase, the tumor cell invades the dermis/hypodermis leading to the endothelium capillaries, which allows access to the bloodstream.2 Key microenvironmental factors play crucial roles in modulating this transformation process, increasing the likelihood of melanomagenesis and progression.2 Metastatic melanoma has a history of being difficult to treat, with low cure and survival rates post-surgical resection and radiation treatment.1,2 Looking closely at the cellular level- cancer cells have the ability to evade apoptosis and grow exponentially without relying on growth factors, angiogenesis, and metastasis.1

Though oncogene-directed therapy proves promising for patients with melanomas harboring BRAF or c-KIT mutations, an estimated half of cases lack such mutations, underscoring the need for further investigation into targeted therapeutic strategies.2,3

Immunotherapies in Melanoma

CTLA-4 (CD152) is a T-cell co-stimulatory protein, which serves as an immune checkpoint that can downregulate immune responses.4  CTLA-4 outcompetes CD28 in binding to CD80 or CD86 on the surface of antigen-presenting cells (APCs), resulting in the inhibition of T-cell maturation and proliferation.4  Monoclonal antibodies targeting the CTLA-4 checkpoint pathway can activate T-cells, thereby enhancing antitumor activity.4

Under normal circumstances, the interaction between PD-1 and PD-L1 (or PD-L2) results in inhibition of the immune response by reducing T-lymphocyte function, inhibiting T-cell activation, proliferation, and cytokine production.4 Many tumor cells express PD-L1 in the attempt to induce negative regulation of T-cells via the PD-1 checkpoint.4  After prolonged activation, T-cells upregulate surface PD-1 expression to which the tumor cells bind, sending an inhibitory signal that deters  apoptosis.4 By blocking the PD-1 and PD-L1 pathways, the antitumor immune response can be restored and T-cells can be activated, becoming more efficient in tumor surveillance.4

PD-1 antagonist monoclonal antibodies add to the possibilities of options to treat metastatic melanoma. Currently, there are monoclonal antibodies designed to prevent PD-1 interaction with its ligands (PD-L1 or PD-L2). Anti-PD-1 monotherapy may be preferable to anti-CTLA monotherapy in some cases; however, combination of the two therapies may increase response and remission rates.5 Of note, this combination of immunotherapies may increase the risk of higher toxicity (GI, hepatic and cutaneous AE).5

Resources and additional reading:

  1. Liu Y, Sheikh S. Melanoma molecular pathogenesis and therapeutic management. Mol Cell Pharmacol. 2014;6(3):228
  2. Paluncic J, Kovacevic Z, et Roads to melanoma: Key pathways and emerging players in melanoma progression and oncogenic signaling. Biochim Biophys Acta. 2016;1863(4):770-784.
  3. Flaherty KT, Hodi FS, Bastian BC. Mutation-driven drug development in melanoma. Curr Opin Oncol. 2010;22(3):178- 183
  4. Jazirehi AR, Lim A, Dinh T. PD-1 inhibition and treatment of advanced melanoma-role of pembrolizumab. Am J Cancer Res. 2016;6(10):2117-2128
  5. Apalla Z, Nashan D, et al. Skin cancer: Epidemiology, disease burden, pathophysiology, diagnosis and therapeutic approaches. Dermatol Ther. 2017 (suppl 1): 5-19
  6. Hodi FD, O’Day SJ et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723