William Wakeland

Background: Metastatic melanoma presents a formidable challenge due to its aggressive nature and dissemination. 325,000 new melanoma cases were diagnosed in 2020. An estimation of 510,000 new cases per year is predicted by 2040¹. Despite advancements in treatment modalities and the  high incidence of the disease, metastatic melanoma remains associated with poor prognosis and limited therapeutic options. 40.5% of patients with a metastatic melanoma were fatal, with the most common metastasis site being the central nervous system (CNS)². The unique tissue microenvironment of the CNS is a significant factor homing the metastatic melanoma cells to the CNS and suppressing immune response. Within the CNS metastasis, patients with metastatic brain melanoma (MBM) patients have a better prognosis and slower disease progression than those with leptomeningeal metastatic melanoma (LMM). Understanding the intricate landscape of metastasis in melanoma holds paramount importance in tailoring effective therapeutic strategies and improving patient outcomes. This review discusses the mechanism by which metastatic melanoma exhibits metastatic site-specific immune responses, and significant difference in outcomes between MBM and LMM.

Objective: To investigate whether the unique pressures of the brain and leptomeninges contributes to the activity of immune cells to identify and eliminate cancer cells.

Search Methods: An online search in the PubMed and the Frontiers in Oncology &Microbiology databases using the keywords: “metastatic melanoma, leptomeningeal metastasis, brain metastasis, ”

Results. Metastatic melanoma, and many other cancers, exhibit metastatic site-specific pathological features. The amplification of MYC, YAP1, and MMP13 genes with downregulation of CDKN2A/B are the most significant changes associating with the CNS metastasis³, which differed from the primary tumor and other organ metastasis. Brain and leptomeningeal metastasis exhibit different responses to immunotherapies. Leptomeningeal metastasis derived from lung cancer demonstrated enhanced immune evasion from Gefitinib than the primary tumor. Increased MET gene copy numbers were associated with this increased immune suppressive ability⁴. One theory is that this different immune response may be due to a unique immune response of the leptomeninges compared to the brain. Recently, it was found that LMM recruited a higher proportion of CD4+ cells compared to brain and surrounding lymph node metastases. It is hypothesized that the MBM specific presence of DC3 dendritic cells affects CD4+ cell recruitment.  Tumors with DC3 presence had more CD8+ cell recruitment, and high expression of specific cytokines and chemokines that serves as chemoattractant for CD8+ cells^5,6. Since the immune response in MBM is stronger than in LMM and the MBM patients have a better prognosis than MBM patients, it is important to understand why DC3 cells only present in MBM. It is likely that cancer cells in the leptomeninges uniquely suppress DC3 proliferation, and therefore, poor immune responses, which lead to poor prognosis outcomes. More research is needed to understand how the LMM microenvironment suppresses DC3 proliferation, and thus, immune response.

Work Cited:

1. Arnold M, Singh D, Laversanne M, et al. Global Burden of Cutaneous Melanoma in 2020 and Projections to 2040. JAMA Dermatol. 2022;158(5):495-503. doi:10.1001/jamadermatol.2022.0160
2. Sandru A, Voinea S, Panaitescu E, Blidaru A. Survival rates of patients with metastatic malignant melanoma. J Med Life. 2014;7(4):572-576.
3. Shih DJH, Nayyar N, Bihun I, et al. Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma. Nat Genet. 2020;52(4):371-377. doi:10.1038/s41588-020-0592-7
4. Nanjo S, Arai S, Wang W, et al. MET Copy Number Gain Is Associated with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR-mutant Lung Cancer. Mol Cancer Ther. 2017;16(3):506-515. doi:10.1158/1535-7163.MCT-16-0522
5. Mabrouk N, Tran T, Sam I, et al. CXCR6 expressing T cells: Functions and role in the control of tumors. Front Immunol. 2022;13:1022136. doi:10.3389/fimmu.2022.1022136
6. Smalley I, Chen Z, Phadke M, et al. Single cell characterization of the immune microenvironment of melanoma brain and leptomeningeal metastases. Clin Cancer Res Off J Am Assoc Cancer Res. 2021;27(14):4109-4125. doi:10.1158/1078-0432.CCR-21-1694