Amplification Profiling Identifies a Subtype of Melanoma Associated With Poor Survival and an Immunosuppressive Tumor Microenvironment.

BACKGROUND

Although melanoma is generally regarded as an immunogenic cancer that will respond to immune checkpoint inhibitors (ICIs), melanomas with amplification respond poorly to these therapies. Further understanding how amplification impacts the effectiveness of ICI therapy is important for the design of future clinical trials.

METHODS

We used data from tumor samples taken from Chinese patients with melanoma analyzed at the Geneplus Institute (=302), as well as data from the Cancer Genome Atlas (TCGA) database (=367) and the Memorial Sloan Kettering Cancer Center (MSKCC) database (=350) to estimate the prevalence of amplification in melanoma, interrogate the relationship between amplification and survival in patients with melanoma, and explore the molecular mechanisms of amplification. We also established a murine model of melanoma harboring amplification and utilized RNA-seq to verify the findings from human tissue samples.

RESULTS

Data from all three sources revealed a low frequency of amplification co-occurring with , , , and mutations. Data from TCGA did not show a statistically significant correlation between amplification and prognosis, irrespective of ICI use. In contrast, the MSKCC cohort showed that amplification was an unfavorable prognostic factor for patients with melanoma, especially for patients who received ICIs and had a high tumor mutation burden (TMB). The TCGA data showed that amplification was associated with a higher proportion of immunosuppressive cells (Treg cells and M2 macrophages) and a lower proportion of immune boosting cells (follicular helper T cells naïve B cells, CD8 T cells). Murine models supported the association between a suppressive immune microenvironment and amplification; tumors with amplification had reduced mRNA expression of CD8, Gzm, B2m and Tap1, significantly higher proportions of resting CD4 memory T cells and significantly lower proportions of plasma cells, CD8 T cells, and T follicular helper cells. Furthermore, a Gene Set Enrichment Analysis (GSEA) analysis of data from the TCGA database suggested that signaling pathways involved in oxidative phosphorylation, reactive oxygen species, adipogenesis, fatty acid metabolism, DNA repair, and Myc targets were differentially enriched in melanoma tumors with amplification. Finally, we observed a notable reduction in levels of angiogenesis-related molecules (encoded by , , , , and ) in a high amplification group from the TCGA database.

CONCLUSIONS

Melanoma with amplification is an independent genomic subtype associated with a poor prognosis, an immunosuppressive TME, activated oxidative and lipid metabolism, and down-regulated angiogenesis. Therefore, avoiding ICIs and antiangiogenic agents, while employing CDK4/6 inhibitors alone or in combination with ICIs, and targeting oxidative and lipid metabolism pathways, may be effective therapeutic strategies for melanoma patients harboring amplification.