Characterizing the immunosuppressive tumor microenvironment in ecDNA positive cutaneous melanoma
Skin cutaneous melanoma (SKCM) is one of the most aggressive types of skin cancer, commonly harboring mutually-exclusive driving mutations in one of the three genes: BRAF, NRAS, and NF1. SKCM tumors that do not contain oncogenic mutations in these genes are designated triple wild type (TWT) melanoma. Various types of cancer, including SKCM, can contain amplified circular DNA segments called extrachromosomal DNA (ecDNA). While it is known that ecDNA plays a role in cancer progression, less is known about its impact on the tumor microenvironment (TME). We characterized the TME of ecDNA(+) SKCM tumors by performing cell deconvolution and enrichment analyses on bulk tissue RNA sequencing. We then computationally predicted patient response to immune checkpoint blockade (ICB) therapy. Our analyses show that ecDNA(+) tumors exhibit lower levels of tumor immune infiltration than ecDNA(-) tumors. While there was no significant difference in the tumor mutation burden between ecDNA(+) and ecDNA(-) tumors, there was significantly lower expression of class I HLA genes. This suggests lower neoantigen presentation by class I HLA genes may lead to reduced immunogenicity of ecDNA(+) tumors. Finally, ecDNA(+) tumors displayed downregulation of immune checkpoints and their respective ligands, and computational prediction indicated a reduced likelihood of a response to ICB among ecDNA(+) patients. Given this, ecDNA may confer ICB resistance to the cancer, suggesting that ecDNA could potentially serve as a biomarker for guiding PD-1 and CTLA4 ICB treatment in SKCM.
