Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden

Abstract

Skin melanoma cells are tightly interconnected with their tumor microenvironment (TME), which influences their initiation, progression, and sensitivity/resistance to therapeutic interventions. An immune-active TME favors patient response to immune checkpoint inhibition (ICI), but not all patients respond to therapy. Here, we assessed differential gene expression in primary and metastatic tumors from the TCGA-SKCM dataset, compared to normal skin samples from the GTEx project and validated key findings across 4 independent GEO datasets, as well as using immunohistochemistry in independent patient cohorts. We focused our attention on examining the expression of various immune receptors, immune-cell fractions, immune-related signatures and mutational signatures across cutaneous melanomas with diverse tumor mutation burdens (TMB). Globally, the expression of most immunoreceptors correlated with patient survival, but did not differ between TMBhigh and TMBlow tumors. Melanomas were enriched in “naive T-cell”, “effector memory T-cell”, “exhausted T-cell”, “resting Treg T-cell” and “Th1-like” signatures, irrespective of their BRAF, NF1 or RAS mutational status. Somatic mutations in IDO1 and HLA-DRA were frequent and could be involved in hindering patient response to ICI therapies. We finally analyzed transcriptome profiles of ICI-treated patients and associated their response with high levels of IFNγ, Merck18, CD274, CD8, and low levels of myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs) and M2 macrophages, irrespective of their TMB status. Overall, our findings highlight the importance of pre-existing T-cell immunity in ICI therapeutic outcomes in skin melanoma and suggest that TMBlow patients could also benefit from such therapies.

Assessment of tumoral and peritumoral inflammatory reaction in cutaneous malignant melanomas

“…The tumor cells create a tumor microenvironment that, as a whole, is the environment that develops around a tumor and includes the extracellular matrix, fibroblasts, blood vessels, lymphatic vessels, stromal cells (T-lymphocytes, B-lymphocytes, neutrophils, leukocytes, dendritic cells, MCs). All these constitute an ecosystem in which they bidirectionally interact with tumor cells, modulating the malignant phenotype [ 52 , 53 ]. Tumor microenvironment often presents an inflammatory aspect and plays an important role in carcinogenesis, by increasing the proliferation of mutant cells.…”

Current Treatment of Melanoma Brain Metastases

“…Today, the contribution of immunohistochemistry and the genetic analysis of tumors to the diagnostic process is becoming increasingly important. Melanoma is one of the most immunogenic cancers and one of the tumors with the highest mutational burden [ 29 , 30 , 31 ]. Molecular profiling plays a key role in the management of malignant melanoma, particularly in the search for new drug targets and the possible personalization of therapy.…”