Project Funding Details

Cancer progression and metastatization is a complex process in which genetic alterations were initially demonstrated to assume a significant role; however, more recent evidence point to tumor microenvironment (TME) and host's immune system as additional players in cancer progression. In this already multifaceted scenario, epigenetic dysregulations are most recently emerging as potential novel hallmarks of cancer metastatization. Indeed, a reciprocal interplay between tumor epigenome and genetic alterations is being suggested, and different TME components are being identified as signals capable to modulate cancer epigenome and immune cells trafficking at tumor sites. Epigenetic events are also increasingly recognized to down-regulate cancer immunogenicity and host's tumor immune recognition, thus providing cancer cells with additional immune escape mechanisms ultimately contributing to their metastatization, and to therapeutic failure of immune check-point(s) blocking (ICB) drugs. Key hypotheses: i) Epigenetically-driven cancer immune-modeling events, potentially shared among different tumor types, may represent key mechanistic links among different compartments (i.e., effector immune cells, tumor, and TME) contributing to cancer metastatization and progression, and to primary and secondary resistance to ICB; ii) Pharmacological targeting of cancer cells, TME and immune system epigenome can dynamically re-shape tumor-TME cross-talk, inhibit tumor progression, remodel immune responses towards effective anti-tumor immunity, and reverse ICB resistance. Noteworthy, upcoming results of our unique epigenetic immune-sequencing NIBIT-M4 clinical trial support this hypothesis, suggesting that tumor epigenome remodeling is a feasible and promising therapeutic intervention in metastatic disease. Key aims: i) In-depth characterization of epigenetically-regulated mechanism(s) regulating the functional "immune-relationship(s)" among tumor, TME, and immune cells contributing to cancer metastatization, progression, and resistance to ICB; ii) Providing mechanistic insights to the role of altered epigenetic regulation and of specific epigenetic-modifier genes in promoting tumor progression and resistance to immunotherapy; iii) Developing innovative combinations of epigenetic drugs with ICB. Integrated epigenome, transcriptome, and mutational landscape analyses of melanoma, mesothelioma and glioblastoma (GBM) tissues will be developed to: a) establish correlations with tumor progression and metastasis, tumor immune contextures, and resistance to immunotherapy; b) identify new pharmacologically targetable pro-metastatic and immunosuppressive epigenetic processes and epigenetic modifier genes. In-vitro and in-vivo models will be used to test whether pharmacological targeting of tumor and immune system epigenome can re-shape the tumor-TME cross-talk towards effective anti-tumor immunity. Hypothesis-driven, epigenetically-based ICB combinatorial trials will be implemented in metastatic melanoma, mesothelioma and GBM. Key foreseeable achievements: i) Definition of integrated profiles (epigenome/gene expression/mutational profile/immune contexture) identifying patients at differential risk of tumor progression for a personalized clinical care; ii) Rescuing responsiveness to ICB of metastatic patients, thus addressing an extremely urgent clinical need; iii) Selection of most appropriate candidates to current and novel ICB; iiii) Identification of highly-innovative, epigenetically-based "personalized" ICB regimens in melanoma, and subsequently in mesothelioma and GBM where the ICB efficacy is beginning to be explored. Identifying druggable, epigenetically-driven, immune dysregulation mechanism(s) sustaining cancer metastatization and resistance to ICB, will provide substantial practical benefits to advanced cancer patients, improving their comprehensive clinical management and providing the scientific basis for "patient-tailored" immunotherapeutic strategies.