Exploring the Molecular Landscape of Cutaneous Melanoma

Cutaneous malignant melanoma (CMM) is one of the most aggressive skin malignancies with poor prognosis
for the patients with metastatic disease. Earlier studies have highlighted the existing molecular diversity
amongst CMM tumors. Such diversity does not result from the malignant cells alone but a product of multitude
of complex interactions among the melanoma and non-melanoma cells in the tumor microenvironment. The
studies included in this thesis aims to shed light on some aspects of this observed diversity, chiefly the roles of
the tumor-enriching immune cells and melanoma cell phenotypes.
In study I, we have identified immune cell-type associated DNA methylation patterns that have offered important
molecular and prognostic information for the metastatic melanoma (MM) tumors. Additionally, these immune-methylation
patterns highlighted the existing microenvironmental resemblance among tumor types with diverse
tissue-of-origin. We further explored the immune-microenvironment of MM tumors using single-cell RNAsequencing
derived marker genes and devised transcriptomic scores for the underlying major immune celltypes
in study II. These immune cell-type scores were found to have prognostic implications and were predictive
of treatment benefit from immunotherapy. In study III, we investigated predictive biomarkers for the treatment
benefit to adoptive T cell (ACT) therapy. Our analyses revealed that tumor mutational and putative neoantigen
burden together with immune enrichment, could work as a composite biomarker to predict treatment benefit
and patient survival upon treated with ACT.
Plasticity of the melanoma cell phenotypes has garnered significant attention in recent times, especially as a
possible mechanism of secondary resistance to targeted treatments. Epigenetic mechanisms such as DNA
methylation is well-known to play a major role in the transcriptional process and their involvement have been
highlighted in context of cancers as well. In study IV, we analyzed the possible contribution of the DNA
methylation to modulate expression of the important melanoma-associated genes such as MITF and SOX10.
Our results indicated that both these genes are likely to be transcriptionally modulated through DNA hypermethylation
of their promoter regions and subsequently help the underlying cells to exhibit a more proliferative,
invasive and treatment-resistant phenotype.
Studies in this thesis have helped to unravel the existing molecular diversity in the CMM tumors and could
potentially motivate the exploration of new therapeutic strategies.