Meng Wang from our affiliated Figueiredo Lab (MIORG) successfully defended her PhD thesis “Novel Immune and Genetic Drivers of Melanoma: Integrative and New Preclinical Models to Uncover the Impact of New Chromosomal and Transcriptomic Changes on Tumor Progression and Immunity” on Monday the 9th of June 2025. Her opponent was Professor Roger Chammas, Head of the Center for Translational Research in Oncology at the Institute of Cancer of São Paulo and Professor of Oncology at the University of São Paulo, Brazil.

Warmest congratulations, Mona!

Summary of the Dissertation:

Melanoma is a genetically unstable cancer that frequently escapes immune surveillance and resists immune checkpoint therapies (ICT), particularly in its uveal (UM) and cutaneous (CM) subtypes. While revolutionary treatments have emerged, many patients fail to respond or develop resistance, highlighting the need to better understand the molecular and immunological drivers of therapy failure and tumor progression.

In the work presented in this dissertation, a multidisciplinary and reverse translational approach was applied to identify key immune and genetic mechanisms associated with melanoma aggressiveness. Tumors with poor response often showed reduced expression of antigen presentation molecules, especially β2-microglobulin (β2M). Integrative analysis of CM tumors revealed a network of β2M-associated genes, with CD1D—a molecule critical for natural killer T (NKT) cell function—emerging as a central component. Epigenetic profiling indicated that methylation regulates both β2M and CD1D expression, suggesting that epigenetic silencing may contribute to immune evasion in resistant CM tumors. These findings propose that loss of β2M may impair anti-tumor responses not only through reduced MHC-I–mediated CD8⁺ T cell activity, but also by disrupting CD1D-dependent NKT cell surveillance. This dual mechanism of immunoevasion opens new avenues for future studies aimed at restoring both cytotoxic and innate-like immune functions in CM.

To further dissect immune resistance in melanoma, the study also focused on UM, a melanoma subtype considered universally refractory to ICT. Among UM patients from a Southeast Asian cohort, chromosomal analyses revealed distinct features, including less frequent monosomy 3 and more frequent chromosome 1q gains—both associated with reduced progression-free survival. A key driver of UM progression, the loss of the tumor suppressor BAP1, was found to underlie these aggressive phenotypes. To investigate its functional consequences in vivo, a CRISPR-engineered, immunocompetent mouse melanocyte model lacking BAP1 was developed. This model exhibited immune suppression and lipid metabolic reprogramming, mirroring high-risk human UM. It offers a robust platform to study BAP1-driven immunometabolic alterations and to test novel immunotherapy combinations targeting these vulnerabilities.

Together, these complementary findings bridge molecular and epigenetic alterations with immune escape mechanisms in melanoma. By modeling BAP1 loss in melanocytic tumors, this dissertation offers a unified framework that integrates patient-derived data with mechanistic understanding, laying the foundation for future combinatorial immunotherapy strategies targeting cancers driven by BAP1 loss.