Madeline Frizzell

Introduction. Melanoma is a rare form of skin cancer in which melanocytes develop into malignant cells that can spread to other parts of the body. While melanoma’s 5-year survival rate is around 98.4% when found in the first stage, the statistics drop significantly with stage IV being around 15-20%¹. The most important cause for melanoma is considered to be intense intermittent UV exposure, which causes damage to the melanocyte’s genome as well as damage to the DNA repair system². Genetic risk factors have shown a link to melanoma, including mutations in CDKN2A, CDK4 and chromosome 1 (1p22)³. The normal immune response to cancerous melanocytes is through cytotoxic T lymphocytes attacking melanosomal proteins presented on MHC class I, resulting in apoptosis⁴. This discussion focuses on the effects of the immunoinhibitory receptor, programmed death receptor 1 (PD-1) which is expressed on many adaptive and innate immune cells as well as the melanocytes themselves. PD-1/PD-L1 interaction controls immune hyperactivity by inhibiting the T cell from undergoing activation⁴. Studies have found that PD-1/PD-L1 interactions not only play a role in limiting the adaptive immune response to melanoma, but promote cancer survival outside of this response due to upregulation of mTOR signaling pathway in the melanocytes⁵. Current advances show antibodies targeting this receptor/ligand interaction can suppress tumor growth. Methods. Articles from 2014-2018 were analyzed and compiled into this review to study the PD-1/PD-L1 interaction, specifically outside of the adaptive immune response. Strains of immunodeficient mice with melanoma were utilized to demonstrate tumor growth inhibition of PD-L1 antibody independently of adaptive immunity. Biopsies were stained for the PD-1 surface protein and then checked for the presence of CD-45, the pan-lymphocytic marker, and CD-31, the endothelial marker. The melanoma tumors were then injected with anti-PD-L1 and biopsied to compare the effect of the antibody on tumor growth⁵. Results. Presence of PD-1 on the tumor without CD-31 or CD-45 indicates that melanoma cells can express this receptor. Following the biopsy, immunohistochemical stains revealed a decrease in p-S6 expression (part of the mTOR signaling pathway), as well as a decrease in tumor volume⁵. Conclusions. The first in-human immunoglobulin G4 (IgG4) PD-1 immune checkpoint inhibitor antibody that disrupts the interaction of PD-1 receptor with its ligand PD-1 and PD-2 was created, Nivolumab⁶. Patients with stage iV melanoma were treated with this antibody and reduction of the tumor was shown in 31% of patients with adverse effects being minimal and minor⁷.

1. Types of Melanoma. Skin Cancer Foundation. https://www.skincancer.org/skin-cancerinformation/melanoma/types-of-melanoma. Accessed May 11, 2018.
2. Khan AQ, Travers JB, Kemp MG. Roles of UVA radiation and DNA damage responses in melanoma pathogenesis. Environmental and Molecular Mutagenesis. 2018. doi:10.1002/em.22176. – UV DAMAGE
3. Testa U, Castelli G, Pelosi E. Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells. Medical Sciences. 2017;5(4):28. doi:10.3390/medsci5040028. – GENETICS
4. Passarelli A, Mannavola F, Stucci LS, Tucci M, Silvestris F. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget. 2017;8(62). doi:10.18632/oncotarget.22190. – TYPICAL IMMUNE RESPONSE
5. Kleffel S, Posch C, Barthel S, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015;162(6). – RESEARCH
6. Selby MJ, Engelhardt JJ, Johnston RJ, et al. Correction: Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology. Plos One. 2016;11(11). doi:10.1371/journal.pone.0167251. – NIVOLUMAB
7. Topalian S, Sznol M, McDermott D, et al.. Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. J Clin Oncol. 2014;32(10):1020-1030.